Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication YERVOY is a human cytotoxic T-lymphocyte antigen 4 (CTLA-4)-blocking antibody indicated for: Melanoma • Treatment of unresectable or metastatic melanoma in adults and pediatric patients 12 years and older as a single agent or in combination with nivolumab. FDA label
Also known as MDX-010 (CTLA-4), Ipilimumab, BMS-734016, Yervoy, Intratumoral Ipilimumab, MDX-CTLA-4, monoclonal antibody CTLA-4
MDX-010 · 71 trials · 77 indications
BICR-assessed Progression-free survival (PFS) is defined as the time from the randomization date to the date of first objectively documented disease progression per RECIST 1.1 (i.e, radiologic) or death due to any cause, whichever occurs first.
BICR-assessed Progression-free survival (PFS) is defined as the time from the randomization date to the date of first objectively documented disease progression per RECIST 1.1 (i.e, radiologic) or death due to any cause, whichever occurs first.
OS was defined as the time from randomization to the date of death from any cause. OS was censored on the last date a subject was known to be alive. Survival follow-up was to be conducted every 3 months after participants's off-treatment date.
Two-year survival rate is defined as the probability that a subject is alive at 2 years following the randomization date and will be estimated via the Kaplan-Meier (KM) method.
RFS is defined as the time between the date of randomization and the date of first recurrence (local, regional or distant metastasis), new primary melanoma, or death (whatever the cause), whichever occurs first.
OS is defined as the time from the date of randomization until the date of death. For those participants who have not died, OS was censored on the last date the participant was known to be alive.
Overall Survival was defined as the time from the date of randomization until the date of death from any cause. For participants without documentation of death, OS was censored on the last date the participant was known to be alive.
Overall Survival (OS) was defined as the time from randomization to the date of death. Participants that had not died were censored at last known date alive. Median OS time was calculated using Kaplan-Meier Estimates. Analysis for the Primary Endpoint occurred when the following 2 conditions were both met: (1) 518 deaths were observed in randomized participants treated with at least one dose of blinded study therapy and (2) 705 deaths were observed in all randomized participants.
OS was defined as the time from the date of randomization until the date of death. For participants without documentation of death, OS was censored at the last date the participant was known to be alive.
The overall survival (OS) rate is a percentage, representing the fraction of all randomized participants who were alive following treatment, from 1 to 5 years. OS was defined as the time between the date of randomization and the date of death as a result of any cause. Survival rates were determined via Kaplan-Meier estimates.
Recurrence free survival (RFS) was programmatically determined based on the disease recurrence data provided by the IRC and was defined as the time between the date of randomization and the date of first recurrence or death (whatever the cause), whichever occurred first. A participant who died without reported recurrence was considered to have recurrence on the date of death. For those participants who remained alive and recurrence-free, RFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, RFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. Computerized tomography (CT) and magnetic resonance imaging (MRI) were mandatory to establish recurrence. The primary analysis was event-driven and planned when at least 512 RFS events assessed per IRC were collected.
Recurrence was defined as appearance of one or more new melanoma lesions: local, regional or distant metastasis. Computerized tomography (CT) and magnetic resonance imaging (MRI) were mandatory to establish recurrence. A participant who died without reported recurrence was considered to have recurred on the date of death. Disease was assessed at randomization and every 12 weeks (±2 weeks) for 3 years, then every 24 weeks until documented distant progression.
Yearly recurrence-free survival rates, eg. at 1 year, defined as the probability that a participant was recurrence-free at 1 year following randomization, were estimated for each treatment group using the Kaplan-Meier product-limit method, along with their corresponding log-log transformed 95% confidence intervals. RFS was defined as the time between the date of randomization and the date of first recurrence or death (whatever the cause), whichever occurred first. A participant who died without reported recurrence was considered to have recurrence on the date of death. For those who remained alive and recurrence-free, RFS was censored on the date of last evaluable post-randomization tumor assessment. For those who remained alive and had no recorded post-randomization tumor assessment, RFS was censored on the day of randomization. Participants with disease at baseline were considered to have an event on the day of randomization. CT and MRI were mandatory to establish recurrence.
The primary outcome of this study is the hazard ratio for progression-free survival (PFS), defined from the date of randomization until the date of progression (PFS truncated at subsequent systemic therapy) as determined by RECIST 1.1, or death due to any cause, whichever comes first. All attempts will be made to follow-up patients for the primary outcome measure for at least one year, even if a patient stops treatment. Patients who do not have a primary outcome event at the time of analysis will be censored on the last date the patient can be confirmed as alive and progression-free.
Clinical benefit was assessed on the basis of clinical response per the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria: * Complete response (CR) = Disappearance of all target lesions; all lymph nodes \< 10 mm on the short axis; no new lesions. * Partial response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions; no new lesions. * Stable disease (SD) = Small changes that do not meet any of the above criteria; no new lesions. * Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s). Clinical benefit was defined as CR + PR. The primary outcome is expressed as the total number of participants who receive clinical benefit within 14 weeks, a number without dispersion. Rates of all clinical responses are reported.
Radiologic disease assessment performed at 12 weeks after initial treatment and then every 6 or 12 weeks. These radiologic disease assessments are evaluated per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 guidelines. This will be conducted by cohort ((1) ACC, (2) Non-urothelial bladder/upper tract cancer and (3) other rare GU tumors)
Events are defined as death by any cause, muscle-invasive, upper urinary tract, nodal or distant recurrence, cystectomy, or switch to cisplatin-based chemotherapy.
Undetectable PSA (prostate-specific antigen) defined as PSA ≤ 0.2 ng/mg after initiation of ipilimumab therapy. Provided with the exact 95% confidence interval. PSA response as recommended by the Prostate Cancer Clinical Trials Working Group (PCWG2) definitions. Percentage can take on values between 0% and 100%.
Percentage of patients alive at 1-year from first dose of treatment.
The primary endpoint is the pathological response rate at surgery (between days 43 and 56) from the first dose of neoadjuvant study treatment for each of cohorts 1b, 2 and 3. The pathological response is categorised thus: - Complete pathological response (pCR) - 0% viable tumour cells in the surgical specimen - Near complete pathological response - (near pCR) - \<10% viable tumour - Partial pathological response (pPR) - 10%-50% viable tumour - No pathological response (pNR) - \>50% viable tumour The proportion of participants with a pCR, or near pCR will determine the pathological response rate.
Assess Pathologic Response (major pathologic response and complete pathologic response) following neoadjuvant low dose SBRT, Ipilimumab and Nivolumab.
Clinical benefit rate for whole population (CR (complete response)+PR (partial response) assessed by radiographic evidence in accordance with RECIST 1.1 criteria
Progression-free survival based on clinical or radiographic evidence of progressive disease according to RECIST 1.1 criteria at 6 months.
Incidence of treatment-emergent adverse events will be assessed according to the latest "Clavien- Dindo Classification of surgical complications" and Common Terminology Criteria of Adverse Events (CTCAE).
Progression-free survival (PFS) per Modified Response Evaluation Criteria in Solid Tumors (RECIST) as determined by blinded independent central review (BICR) assessed by radiologic assessments
Proportion of patients dead at one year from randomisation and whose immediate cause of death is neurological.
Persistent PR or CR is defined per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 guidelines. Radiologic disease assessment was performed every 8 weeks after patients discontinued nivolumab induction therapy. At 1 year after nivolumab discontinuation, the percentage of patients with persistent PR and CR were reported (for Arm A only).
Response is defined per Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 guideline. After initiation of ipilimumab, Arm B patients underwent imaging after the first 12 weeks and then every 8 weeks until disease progression. Best overall response during Arm B treatment were summarized with 90% confidence interval.
Clinical benefit rate for whole population (CR (complete response)+PR (partial response)+SD (stable disease)\>3 months)
Overall Response Rate was defined as any participant who had a Complete Response (CR) or Partial Response (PR) as defined by RECIST v1.1 by week 18 of treatment.
Intracranial Clinical Benefit Rate (CBR) is defined as the percentage of all treated participants whose best overall response is either a complete response (CR) or partial response (PR) or whose best overall response was Stable Disease (SD) with duration of \>6 months, as determined by modified RECIST 1.1 criteria for index intracranial lesions based on investigator review.
rPFS was defined as the time from the date of randomization until the date of disease progression based on radiographic evidence and/or death from any cause, whichever occurs first. Radiographic disease progression is defined as: Confirmed bone disease progression according to criteria adapted from the Prostate Cancer Clinical Trials Working Group 2 (PCWG2), OR Non-bone disease progression according to the modified Response Evaluation Criteria In Solid Tumors (RECIST) 1.1. After termination of the study, collection of tumor assessments and other data to support the efficacy analyses was no longer required in patients who discontinued study treatment. As a result, the presented efficacy results are based on limited data. The number of participants with reported radiographic progression is shown.
Immune response will be tested using the single sample binomial exact test when induction therapy is completed. The Immunoglobulin M (IgM) and Immunoglobulin G (IgG) antibody responses to PAP and/or PA2024 will be assessed by ELISA assay at baseline and week 20 after start of sipT treatment (day 113 of study treatment). A positive response is defined as a titer \> 1:400. The positive immune percentage for both IgG and IgM antibodies to PAP and to PA2024 will be used to summarize the results for each study arm.
Immune Response Adverse Events (IRAEs) will be reported for each study arm by tabulating the frequency of the maximum grade occurring for each patient for each type of iRAE using NCI Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0. IRAEs will be reported as a proportion of the participants in the treatment arm with the associated highest grade IRAE occurrences during protocol therapy.
Objective Response Rate (ORR) is defined as the number of randomized participants who achieve a best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR), based on investigator assessments \\\[using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1\\\], divided by the number of all randomized participants. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \\\<10 mm. Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
AEs graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death. Related=relationship to study drug reported as certain, probable, possible, or missing. Immune-related AEs (irAEs) characterized by potential association with inflammation and considered by investigator as drug related. Primary endpoint (PE) includes results from Day 1 to 12 weeks after initial dose of last participant. Data evaluated at PE last patient, last visit (LPLV).
Survival rate=percentage of participants surviving at 1 year following start of study drug. Every effort was made to collect survival data on all patients, including those withdrawn from treatment for any reason. If the death of a patient was not reported, the patient's last known alive date was recorded. Confidence intervals were computed using the Clopper-Pearson method.
AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Drug-related=having certain, probable, possible, or unknown relationship to study drug. Grading criteria for AEs: Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Life-threatening or disabling, Grade 5=Death.
AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade 1=Mild, Grade 2=Moderate, Grade 3=Severe, Grade 4=Potentially Life-threatening or disabling.
irPFS is defined as the time between the randomization date and the time of disease progression per irRC or death, whichever occurs first. irRC criteria=Measurable new lesions: incorporated into the tumor burden (eg, added to the index lesions); do not define progression unless the total measurable tumor burden increases by the required amount (25%). New non-measurable lesions: not considered progression if the total measurable tumor burden is stable or shrinking. irPFS was measured in months.
To determine the median overall survival of patients with advanced/metastatic urothelial cancer treated with gemcitabine, cisplatin, plus ipilimumab, calculated from the date of registration until the date of final analysis, projected to be 48 months from the start of the study.
Immune-related Disease Control Rate (irDCR) is the proportion of treated subjects with a BOR of confirmed irCR, confirmed irPR or irSD. Tumor assessment (including determination of overall response at each tumor assessment and best overall response (BOR) taken over all tumor assessments prior to subsequent therapy is performed using the immune-related (ir) tumor response criteria.
Disease control rate is defined as the number of patients with a best overall response of complete response (CR), partial response (PR), or stable disease (SD) (global, in brain, or outside of brain) based on mWHO criteria divided by the number of patients who received treatment. By mWHO criteria: CR=complete disappearance of all index lesions. PR=decrease, relative to baseline, of 50% or greater in the sum of the 2 largest perpendicular diameters of all index lesions. SD=does not meet criteria for CR or PR, in the absence of progressive disease (PD). Patients with PR or CR not confirmed after at least 4 weeks are scored as SD unless they have new primary lesions. PD=at least 25% increase in the sum of the diameters of all index lesions (taking as reference the smallest sum recorded at or following baseline) and/or the appearance of any new lesions. CNS=central nervous system.
irPFS is defined as the time between the randomization date and date of immune-related Progressive Disease (irPD) (at least 25% increase percentage change in total tumor burden, including new lesions) or death, whichever occurs first. For patients with no recorded postbaseline tumor assessments, irPFS is censored at randomization. Participant who die without reported irPD are considered to have progressed on the date of death. For those who remain alive and have no irPD, irPFS is censored on the date of last evaluable tumor assessment. Independent review committee performed tumor assessment.
An AE is any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. An SAE is a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Drug-related is defined as having certain, probable, possible, or missing relationship to study drug. An IrAE is an AE characterized by a potential association with inflammation and considered by the investigator to be drug related. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death.
Percentage of participants who achieved Complete Response (CR) or Partial Response (PR) according to RECIST criteria. Particularly, CR is defined as disappearance of all target lesions, while PR is defined as at least a 30% decrease n the sum of the longest diameter (LD) of target lesions taking as reference the baseline sum LD.
Percentage of participants who experienced an irAE during the course of the study defined by the induction of Grade 1, Grade 2, or acceptable Grade 3 drug-related irAEs. For the purposes of this trial, acceptable drug-related irAEs are skin-related immune-mediated adverse events \< or = Grade 3 (potentially reversible inflammation \< Grade 4 that can be attributable to a local antitumor reaction that could potentially be a therapeutic response will also be considered an acceptable irAE). Note: The confidence interval was calculated using the Clopper Pearson method
To determine the time (months) from first dose to disease relapse. Time to disease relapse is defined from the start of treatment to the first occurrence of any new lesion (reported by the investigator on physical exam or diagnostic imaging assessments that are attributed to metastatic melanoma) or death. Participants who neither relapse nor died will be censored on the date of their last tumor evaluation. Median estimated using Kaplan-Meier method; A two-sided 95% CI for median in each treatment group was computed via the log-log transformation method.
DLTs recorded and graded according to NCI Common Toxicity Criteria for Adverse Events (CTCAE), version 4.0. for Phase 1B part of study
The proportion of patients who have achieved complete remission as per Lugano criteria which is complete metabolic response even with a persistent mass.
Percentage of patients that underwent surgery within 12 weeks after study start were assessed
The immune-related response criteria (irRC) incorporate several elements reflecting the complex tumor dynamics of ipilimumab/nivolumab treatment. Under these criteria, a measure of tumor volume is used that incorporates the contribution of new measurable lesions. Each net percentage change in tumor burden per assessment using irRC accounts for the size and growth kinetics of both old and new lesions as they appear. New lesions alone do not qualify as immune-related progressive disease.
The immune-related response criteria (irRC) incorporate several elements reflecting the complex tumor dynamics of ipilimumab/nivolumab treatment. Under these criteria, a measure of tumor volume is used that incorporates the contribution of new measurable lesions. Each net percentage change in tumor burden per assessment using irRC accounts for the size and growth kinetics of both old and new lesions as they appear. New lesions alone do not qualify as immune-related progressive disease.
The immune-related response criteria (irRC) incorporate several elements reflecting the complex tumor dynamics of ipilimumab/nivolumab treatment. Under these criteria, a measure of tumor volume is used that incorporates the contribution of new measurable lesions. Each net percentage change in tumor burden per assessment using irRC accounts for the size and growth kinetics of both old and new lesions as they appear. New lesions alone do not qualify as immune-related progressive disease.
The immune-related response criteria (irRC) incorporate several elements reflecting the complex tumor dynamics of ipilimumab/nivolumab treatment. Under these criteria, a measure of tumor volume is used that incorporates the contribution of new measurable lesions. Each net percentage change in tumor burden per assessment using irRC accounts for the size and growth kinetics of both old and new lesions as they appear. New lesions alone do not qualify as immune-related progressive disease.
The percentage of patients with surgery delayed possibly related to the study drug.
Adverse Events (AEs) as characterized by type, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] v5.0), timing, seriousness, and relationship to study treatment.
The two-sample t-test will be used to compare the change in CD8+ T cell infiltration after treatment between each experimental group (Cohort A, B, C, and D) and the control group (cohort E), respectively.
MTD defined as highest dose level with less than 2 patients with dose limiting toxicity (DLT) out of at least six patients in the cohort. All enrolled participants will be considered in the DLT analysis. If at any time more than or equal to one third (33%) of participants at a dose level experience DLT, the MTD will be reassessed and the next lowest dose level for the combination therapy considered the MTD.
Tumor Response will be evaluated using the irRC best response (Partial Response (PR) + Complete Response (CR)). Modified WHO criteria will be used for measurement of tumors. The irradiated lesion will be excluded from the assessment of response.
AEs will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading scale, version 4.0.
which is defined as the time from the start of therapy until the criteria for progression are met
A DLT was defined as study drug-related adverse event occurring during the first 2 cycles after ipilimumab administration in the induction phase and was any of the following: Grade 4 absolute neutrophil count (ANC) decreased (\<500 cells/ mm\^3) for 7 or more consecutive days; febrile Neutropenia (body temperature ≥38.5° C with ANC \<1000 /mm\^3) lasting \>3 days; Grade 4 platelet count decreased (\<25,000 cells/mm\^3) or Grade 3 platelet count decreased requiring a platelet transfusion; Grade 3 or greater nausea, vomiting, diarrhea, despite the use of adequate/maximal medical intervention; Grade 3 or greater aspartate transaminase/alanine transaminase level and rash that has not resolved to Grade 2 or lower within 2 weeks after onset; or any Grade 3 or greater nonhematologic toxicity (except Grade 3 fatigue, Grade 3 asthenia, Grade 3 transient arthralgia/myalgia, or Grade 3 transient abnormal electrolyte levels).
Single-dose Pharmacokinetic (PK) parameters of ipilimumab were derived from serum concentration versus time data. Cmax was measured from first dose to end of the induction period (4 doses) as micrograms per milliliter (μg/mL). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as "missing" for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]).
The single-dose pharmacokinetic parameters of ipilimumab were derived from serum concentration versus time data. AUC(0-21d) was measured from first dose to end of the induction period as micrograms\*hours per milliliter (μg\*h/mL). Samples were obtained at 0 hour (predose) on Days 1, 2, 3, 4, and Weeks 2, 3, 4, 7, and 10; Day 1, samples were also obtained 1 h 30 minutes (min), 2 h, 2 h 30 min, 3 h 30 min, 4 h 30 min, and 6 h post dose. In calculating PK parameters, predose concentrations and concentrations prior to first quantifiable concentration below the lower limit of quantitation (LLOQ) were treated as "missing" for the calculation of summary statistics. Drug was quantitatively determined in serum by an enzyme-linked immunosorbent assay (ELISA). Individual PK parameter values were derived by non-compartmental methods using a validated PK analysis program (Kinetica™ 4.4.1 within eToolbox \[version 2.6.1\]).
Cmax=micrograms per milliliter (µg/mL): drug concentration versus time for ipilimumab (Day 43) and paclitaxel, dacarbazine, and AIC (Days 1, 43). Ipilimumab determined from plasma by Enzyme-linked Immunosorbent Assay (ELISA); lower level of quantitation (LLOQ)=0.8 µg/mL; upper limit of quantitation (ULOQ)=25.6 µg/mL; Day 43=0 hour (h) predose, 1.5, 4.0, 24, 72, 168, 336, 504 h post dose; from Day 162 on every 12 weeks (Day 1 and 22= 0 h). Paclitaxel determined using liquid chromatography tandem mass spectrometry (LC/MS/MS) detection; LLOQ=10 nanograms per milliliter (ng/mL); ULOQ=5000 ng/mL; Day 1 and Day 43=0 h predose, 1.5, 3.0, 3.5, 5,5, 9.5, 24, 48 h postdose. Dacarbazine (DTIC) and AIC determined from plasma using liquid chromatography atmospheric pressure ionization (API) tandem mass spectrometry (LC-API/MS/MS) detection; LLOQ for dacarbazine=10.0 ng/mL; ULOQ=5000 ng/mL; AIC LLOQ=0.05 µg/mL; ULOQ=25.0 µg/mL; Day 1: 0 h predose, 1, 1.5, 2.5, 3.5, 5.5, 9.5, 24 h post dose.
AUC=micrograms\*hour(h) per mL (µg\*h/mL): derived from drug concentration versus time for ipilimumab (Day 43 only) and paclitaxel, dacarbazine, and AIC (Days 1, 43). Ipilimumab determined from plasma ELISA; LLOQ=0.8 µg/mL; ULOQ=25.6 µg/mL; sample times on Day 43=0 hour (h) predose, 1.5, 4.0, 24, 72, 168, 336, 504 h post dose; starting Day 162 every 12 weeks (Day 1 and 22= 0 h). Paclitaxel determined from plasma using LC/MS/MS detection; LLOQ=10 nanograms per milliliter (ng/mL); ULOQ=5000 ng/mL; sample times Day 1 and Day 43=0 h predose, 1.5, 3.0, 3.5, 5,5, 9.5, 24, 48 h postdose. Dacarbazine (DTIC) and AIC determined from plasma using liquid chromatography API tandem mass spectrometry (LC-API/MS/MS) detection; LLOQ for dacarbazine=10.0 ng/mL; ULOQ=5000 ng/mL; AIC LLOQ=0.05 µg/mL; ULOQ=25.0 µg/mL; sample times Day 1: 0 h predose, 1, 1.5, 2.5, 3.5, 5.5, 9.5, 24 h post dose.
AEs graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling, Gr 5=Death. Related=relationship to study drug reported as certain, probable, possible, or missing. Immune-related AE (irAE) was defined as a clinically significant AE of any organ that is associated with drug exposure, of unknown etiology, and is consistent with an immune-mediated mechanism. Day 1=first day of study treatment.
Response by investigator using National Cancer Institute (NCI) PSA Working Group recommendations= PSA \< 50% of PSA reference value occurring on or before Day 85; response confirmed at least 4 weeks after the first measurement. PSA reference=PSA measured immediately prior to treatment. Complete response (CR)=PSA \< 2 nanograms per milliliter (ng/mL), confirmed at least 4 weeks after 1st value; Partial response (PR)=PSA ≤ 50% of PSA reference, confirmed at least 4 weeks after 1st value; Unconfirmed=not confirmed by repeat measurements; Stable disease(SD)=No change from PSA reference; Progressive disease (PD) defined: If PSA nadir was ≥ 100% of the reference: PSA ≥ 125% of PSA reference and with a difference of absolute value of ≥ 5 ng/mL; If PSA nadir was \< 100% and ≥ 50% of the reference: PSA ≥ 125% of PSA nadir and with a difference of absolute value of ≥ 5 ng/mL: If PSA nadir was \< 50% of the reference: PSA ≥ 150% of PSA nadir and with a difference of absolute value of ≥ 5 ng/mL.
| Arm | Type | Description |
|---|---|---|
| Arm A: Nivolumab Monotherapy | EXPERIMENTAL | - |
| Arm B: Nivolumab + Ipilimumab Combination | EXPERIMENTAL | - |
| Arm C: Investigator's Choice Chemotherapy | ACTIVE_COMPARATOR | Participants in Arm C would be allowed to receive Nivolumab + Ipilimumab if they progress |
| Module A | EXPERIMENTAL | Chemotherapy/Biologics combined |
| Module B | ACTIVE_COMPARATOR | Chemotherapy Combination |
| Ipilimumab | EXPERIMENTAL | Intravenously (IV) 3 mg/kg every 3 weeks (at week 1,4,7,10) and thereafter (q3w/4 doses) at the time of progression |
| Dacarbazine | EXPERIMENTAL | IV solution 250 mg/m2 (Day 1-5, every 3weeks/at week 1, 4, 7, 10,13,16,19,22) |
| Ipilimumab and Placebo matching Nivolumab | EXPERIMENTAL | - |
| Nivolumab and Placebo matching Ipilimumab | EXPERIMENTAL | - |
| Arm 1: Carboplatin + Paclitaxel + Ipilimumab | EXPERIMENTAL | Paclitaxel 175 mg/m² IV Solution Every 3 weeks during induction and every 12 weeks during maintenance until disease progression declared by modified WHO (mWHO) Carboplatin Area Under the Curve (AUC6) IV Solution Every 3 weeks during induction and every 12 weeks during maintenance until disease progression declared by mWHO Ipilimumab 10 mg/kg IV Solution Every 3 weeks during induction and every 12 weeks during maintenance until disease progression declared by mWHO |
| Arm 2: Carboplatin + Paclitaxel + Placebo | EXPERIMENTAL | Carboplatin AUC6 IV Solution Every 3 weeks during induction and every 12 weeks during maintenance until disease progression declared by mWHO Paclitaxel 175 mg/m² IV Solution Every 3 weeks during induction and every 12 weeks during maintenance until disease progression declared by mWHO Placebo IV Solution Every 3 weeks during induction and every 12 weeks during maintenance until disease progression declared by mWHO |
| Arm 1: Ipilimumab (3 mg/kg) | EXPERIMENTAL | Ipilimumab 3 mg/kg solution intravenously once every 3 weeks for 4 doses; option for Re-induction, until disease progression or unacceptable toxicity |
| Arm 2: Ipilimumab (10 mg/kg) | EXPERIMENTAL | Ipilimumab 10 mg/kg solution intravenously once every 3 weeks for 4 doses; option for Re-induction, until disease progression or unacceptable toxicity |
| Ipilimumab+Etoposide+Cisplatin/Carboplatin | EXPERIMENTAL | Ipilimumab: IV solution, Intravenous (IV), 10 mg/kg, Once every 3 weeks for 4 doses, then every 12 weeks, Until progression of disease or unacceptable toxicity, or until the maximum treatment period of 3 years is reached Etoposide: IV solution, IV, 100 mg/m2, Days 1-3 every 3 weeks, 4 cycles Cisplatin: IV solution, IV, 75 mg/m2, Once every 3 weeks, 4 doses Carboplatin: IV Solution, IV, Area Under the Curve (AUC) 5, Once every 3 weeks, 4 doses |
| Placebo matching Ipilimumab+Etoposide+Cisplatin/Carboplatin | PLACEBO_COMPARATOR | Placebo matching Ipilimumab: IV solution, IV, 0 mg/kg, Once every 3 weeks for 4 doses, then every 12 weeks, Until progression of disease or unacceptable toxicity, or until the maximum treatment period of 3 years is reached Etoposide: IV solution, IV, 100 mg/m2, Days 1-3 every 3 weeks, 4 cycles Cisplatin: IV solution, IV, 75 mg/m2, Once every 3 weeks, 4 doses Carboplatin: IV Solution, IV, Area Under the Curve (AUC) 5, Once every 3 weeks, 4 doses |
| Ipilimumab + Paclitaxel and Carboplatin | EXPERIMENTAL | Ipilimumab + Active Chemo Backbone Ipilimumab: IV solution, intravenous (IV), 10 mg/kg, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses |
| Placebo + Paclitaxel and Carboplatin | PLACEBO_COMPARATOR | Placebo + Active Chemo Backbone Placebo: IV solution, IV, 0.9% sodium chloride or 5% dextrose, 90 minute infusion, Once every 3 weeks for 4 doses and then every 12 weeks until disease progression (for a maximum treatment period of 3 years from the first dose) Paclitaxel: IV solution, IV, 175 mg/m², 3 hour infusion, Once every 3 weeks for 6 doses Carboplatin: IV solution, IV, Area Under the Curve (AUC) = 6, 30 minute infusion, Once every 3 weeks for 6 doses |
| Placebo | PLACEBO_COMPARATOR | - |
| A | ACTIVE_COMPARATOR | - |
| B | PLACEBO_COMPARATOR | - |
| Arm A: Ipilimumab and Dacarbazine | EXPERIMENTAL | In Maintenance phase: Ipilimumab will be continued. Dacarbazine was given up to Week 22 and is not given in the Maintenance phase |
| Arm B: Placebo and Dacarbazine | ACTIVE_COMPARATOR | - |
| Standard of Care I/N alone | ACTIVE_COMPARATOR | induction ipilimumab 1 mg/kg combined with nivolumab 3 mg/kg (I/N) every 3 weeks for cycles 1-4 followed by maintenance treatment with nivolumab 240mg every 2 weeks or 480mg every 4 weeks until disease progression (as determined by RECIST 1.1), intolerance, or patient/physician decision to stop treatment. |
| Standard of Care I/N plus primary disease SBRT | EXPERIMENTAL | induction ipilimumab 1 mg/kg combined with nivolumab 3 mg/kg (I/N) every 3 weeks for one cycle, followed by SBRT to the primary disease in-situ, prior to cycle 2-4 of I/N. Patients randomized to SBRT will undergo radiation planning during the first cycle of I/N to their primary kidney mass, and then the radiation will be delivered between cycles 1 and 2 to a dose of 30-40 Gy in 5 fractions every other day over 1.5 weeks. Approximately one week following completion of SBRT, patients will start cycle 2 of immunotherapy as per standard of care. The total time elapsed between the start of cycle 1 and 2 of I/N should be no more than 6 weeks. After completion of up to four cycles of I/N, patients will proceed to standard of care maintenance treatment with nivolumab 240mg every 2 weeks or 480mg every 4 weeks until disease progression (as determined by RECIST 1.1), intolerance, or patient/physician decision to stop treatment. |
| Ipilimumab/nivolumab + cryotherapy | EXPERIMENTAL | 1 mg/kg with nivolumab 3 mg/kg every 3 weeks x 4 doses. (One cycle of treatment is 3 weeks). Cryotherapy (cryoablation) will be performed between investigational agent treatment Cycles 1 and 2 |
| Nivolumab+Ipilimumab | EXPERIMENTAL | * Nivolumab and Ipilimumab are administered intravenously every 3 weeks for a total of 4 maximum doses. After combination therapy, nivolumab will be administered as monotherapy every 4 weeks. * Doses are determined per protocol. |
| Induction with heckpoint inhibition followed by consolidative chemoradiation | EXPERIMENTAL | Checkpoint inhibition and chemoradiation |
| Treatment (ipilimumab) | EXPERIMENTAL | Patients receive ipilimumab IV over 90 minutes on day 1. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients without progression then receive maintenance ipilimumab IV once every 3 months for 4 additional doses. |
| Nivolumab and Ipilimumab | EXPERIMENTAL | Nivolumab and Ipilimumab every 3 weeks for a total of four doses (Cycles 1 and 2) followed by Nivolumab every 2 weeks |
| Treatment Arm A | EXPERIMENTAL | Ipilimumab at 3 mg per kg with nivolumab at 1 mg per kg will be administered on days 1 and 22 (Q3W) in the neoadjuvant period for a total of 2 doses. |
| Treatment Arm B | EXPERIMENTAL | Ipilimumab 1mg per kg and the fixed dose combination nivolumab 480 mg and relatlimab 160 mg will be administered on days 1 and 29 (Q4W) for a total of 2 doses. |
| Treatment Arm C | EXPERIMENTAL | Fixed dose combination of nivolumab 480 mg and relatlimab 160 mg alone, to be administered on days 1 and 29 (Q4W) for a total of 2 doses. |
| Treatment Arm D (Cohort 1a) | ACTIVE_COMPARATOR | Ipilimumab at 1 mg per kg with nivolumab at 3 mg per kg will be administered on days 1 and 22 (Q3W) in the neoadjuvant period for a total of 2 doses. |
| Treatment Arm E (Cohort 1b) | ACTIVE_COMPARATOR | Ipilimumab at 1 mg per kg with nivolumab at 3 mg per kg will be administered on days 1 and 22 (Q3W) in the neoadjuvant period for a total of 2 doses. |
| Treatment Arm F | ACTIVE_COMPARATOR | Pembrolizumab 200 mg will be administered on days 1 and 22 (Q3W) in the neoadjuvant period for a total of 2 doses |
| Protocol Therapy | EXPERIMENTAL | Ipilimumab: 1mg/kg IV day 1. Nivolumab: 3mg/kg IV days 1, 15, 29. SBRT delivered as 1-2 fractions to the gross primary tumor and nodal disease following day 1 infusion and completed by day 3 (7Gy x 1; 4Gy x 2). |
| Ipilimumab and Nivolumab | EXPERIMENTAL | All Subjects will be treated with: Nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg concurrently every 3 weeks for 4 doses followed by nivolumab only at 480mg every 4 weeks until progression (up to 2 years) |
| Neoadjuvant Chemoradiotherapy | OTHER | Neoadjuvant Chemoradiotherapy (50 Gy in 2 Gy fractions + Capecitabine 1650 mg/m2/d over 25 working days) |
| Neoadjuvant Chemoradiotherapy, Ipilimumab, Nivolumab | EXPERIMENTAL | Neoadjuvant Chemoradiotherapy (50 Gy in 2 Gy fractions + Capecitabine 1650 mg/m2/d over 25 working days) with sequential Ipilimumab (1 mg/kg IV on day 7) and Nivolumab (3 mg/kg IV on day 14, 28 and 42) |
| Arm A | EXPERIMENTAL | Ipilimumab and nivolumab + UV1 |
| Arm B | ACTIVE_COMPARATOR | Ipilimumab and nivolumab |
| Nivolumab + ipilimumab | ACTIVE_COMPARATOR | Nivolumab 1mg/kg and ipilimumab 3mg/kg Q3W x 4 doses, then nivolumab 480 mg every 4 weeks. Any form of salvage therapy (surgery or radiotherapy) may be administered to either cohort for the treatment of intracranial disease progression. |
| Nivolumab + ipilimumab,concurrent SRS | ACTIVE_COMPARATOR | Nivolumab 1mg/kg and ipilimumab 3mg/kg Q3W x 4 doses, then nivolumab 480 mg every 4 weeks. Stereotactic radiotherapy 16 to 22 Gy in 1 fraction or 24 to 30 Gy, hypofractionated for larger lesions. Stereotactic radiotherapy to commence within 7 days of of the baseline / planning MRI brain. Hypofractionated stereotactic radiotherapy should be completed within 14 day of the first fraction. Any form of salvage therapy (surgery or radiotherapy) may be administered to either cohort for the treatment of intracranial disease progression. |
| Overall cohort: Initial Primary Treatment with Nivolumab (induction phase) | EXPERIMENTAL | * Therapy with nivolumab IV every 2 weeks * Serial imaging assessments every 8 weeks * After confirmatory scans, patients are assigned to Arm A or Arm B. |
| Arm A: Observation Arm (for patients with persistent response to induction nivolumab) | EXPERIMENTAL | Patients with persistent response (complete or partial response) to induction nivolumab are assigned to Arm A (Observation Arm). * Patients discontinued nivolumab after allocation to Arm A. * Serial imaging assessments every 8 weeks. * If scans persistently show PR/CR, patients remained on observation. * If progressive disease develops, therapy with nivolumab (480 mg IV every 4 weeks) will be resumed. * If there is subsequent progression on nivolumab monotherapy, ipilimumab (1 mg/kg IV every 3 weeks x 2 doses) is added. * If progression after nivolumab + ipilimumab, therapy discontinued. If SD/PR/CR, nivolumab is continued until progression. |
| Arm B: Nivolumab+Ipilimumab then nivolumab alone (for patients with SD/PD to induction nivolumab) | EXPERIMENTAL | Patients with confirmed SD/PD to induction nivolumab are allocated to Arm B (Combination Therapy Arm). * In combination therapy, patients received nivolumab 3 mg/kg and ipilimumab 1 mg/kg intravenously every 3 weeks for two doses. * After then nivolumab will be continued at 480 mg IV every 4 weeks until disease progression. * Arm B patients undergo imaging at 12 weeks and then every 8 weeks. |
| Arm 1: Ipilimumab 3 mg/kg | EXPERIMENTAL | Ipilimumab 3 mg/kg injection intravenously every 3 weeks for 4 doses in Induction phase. Subjects that are eligible to receive Ipilimumab in the Maintenance phase will be dosed every 12 weeks for a maximum of 3 years since the first induction dose |
| Arm 2: Ipilimumab 10 mg/kg | EXPERIMENTAL | Ipilimumab 10 mg/kg injection intravenously every 3 weeks for 4 doses in Induction phase. Subjects that are eligible to receive Ipilimumab in the Maintenance phase will be dosed every 12 weeks for a maximum of 3 years since the first induction dose |
| Immediate IpilimumabTreatment | EXPERIMENTAL | Arm 1 (Immediate Treatment) Ipilimumab Q3wks x 4 started 1 day following the final dose of SipT. |
| Delayed IpilimumabTreatment | EXPERIMENTAL | Arm 2 (Delayed Treatment) Ipilimumab Q3wks x 4 started 3 weeks following the final dose of SipT. |
| Nivolumab Monotherapy | EXPERIMENTAL | - |
| Nivolumab + Ipilimumab Cohort C3 | EXPERIMENTAL | - |
| Nivolumab + Ipilimumab + Cobimetinib Cohort C4 | EXPERIMENTAL | - |
| Nivolumab + BMS-986016 Cohort C5 | EXPERIMENTAL | - |
| Nivolumab + Daratumumab Cohort C6 | EXPERIMENTAL | - |
| Arm A: Ipilimumab | EXPERIMENTAL | Ipilimumab Intravenous Injection 3 mg/kg for every 3 weeks upto 4 doses |
| Ipilimumab, 10 mg/kg + Dacarbazine, 850 mg/m^2 | EXPERIMENTAL | During the Induction Period, participants received ipilimumab, 10 mg/kg, as tolerated by intravenous (IV) infusion as 1 single dose during Weeks 1 (Day 1), 4, 7, and 10 for a total of 4 separate doses. During the Maintenance Phase, participants received ipilimumab, 10 mg/kg, as tolerated by IV infusion every 12 weeks, beginning at Week 24, until disease progression or unacceptable toxicity occurred or the patient withdrew consent. Participants also received dacarbazine, 850 mg/m\^2, by IV infusion over 30 to 60 minutes, starting on Week 1 and repeated every 3 weeks until Week 22. Dacarbazine was dosed on the same day as ipilimumab, when applicable, after the ipilimumab dose. |
| Vemurafenib, 960 mg + Ipilimumab, 10 mg/kg | EXPERIMENTAL | Participants received vemurafenib, 960 mg, twice daily for 6 weeks (Vem1 Phase). After a washout period of 3-10 days, patients received ipilimumab, 10 mg/kg, every 3 weeks for a maximum of 4 doses. At Week 24, participants received ipilimumab, 10 mg/kg, every 12 weeks until disease progression or unacceptable toxicity. Patients who did not progress or have unacceptable toxicity in the Vem1 Phase were retreated with vemurafenib (Vem 2 Phase) at the last dose level identified at the end of the Vem1 Phase until disease progression or unacceptable toxicity. |
| Arm: Ipilimumab, 10 mg/kg | EXPERIMENTAL | Participants received 10 mg/kg of ipilimumab administered intravenously once every 3 weeks for 4 doses (Induction Phase). Then, once every 12 weeks (Maintenance Phase), until disease progression or unacceptable toxicity occurs. |
| Arm B: Best Supportive care (BSC) | OTHER | BSC may include the continuation of the Fluoropyrimidine that was used during the lead-in chemotherapy, but no other systemic anti cancer therapy |
| Treatment | EXPERIMENTAL | Gemcitabine 1000 mg/m2 Days 1 \& 8 Cisplatin 70 mg/m2 Day 1 Ipilimumab 10 mg/kg Day 1 (start cycle 3) |
| Single arm of ipilimumab and fotemustine | EXPERIMENTAL | Ipilimumab in combination with Fotemustine |
| Ipilimumab, 10 mg/kg, IV in corticosteroid-free patients | EXPERIMENTAL | Participants who had not received corticosteroid therapy for at least 10 days before starting study drug received ipilimumab,10 mg/kg, as a 90-minute intravenous (IV) infusion every 3 weeks (Weeks 1, 4, 7, and 10) during the Induction Phase. Those eligible (patients who did not discontinue due to toxicity, did not show progression at 24 weeks, and who remained clinically stable) for the Maintenance Phase continued to receive ipilimumab, 10 mg/kg IV, every 12 weeks, beginning at Week 24. |
| Ipilimumab, 10 mg/kg, IV in corticosteroid-dependent patients | EXPERIMENTAL | Participants who were dependent on corticosteroid therapy received ipilimumab, 10 mg/kg, as a 90-minute intravenous (IV) infusion every 3 weeks (Weeks 1, 4, 7, and 10) during the Induction Phase. Those eligible (patients who did not discontinue due to toxicity, did not show progression at 24 weeks, and who remained clinically stable) for the Maintenance Phase continued to receive ipilimumab, 10 mg/kg IV, every 12 weeks, beginning at Week 24. |
| Ipilimumab/ placebo + paclitaxel + carboplatin (concurrent) | EXPERIMENTAL | - |
| Ipilimumab/ placebo + paclitaxel + carboplatin (sequential) | EXPERIMENTAL | - |
| Ipilimumab placebo + paclitaxel + carboplatin | ACTIVE_COMPARATOR | - |
| First reinduction: Ipilimumab, 0.3 to 10 mg/kg | EXPERIMENTAL | Participants who initially received ipilimumab, 0.3 mg/kg, in a parent study received ipilimumab, 10 mg/kg in the current study. Ipilimumab was administered as an individual open-label dose every 3 weeks for the first 10 weeks of reinduction for a total of 4 separate doses unless the patient experienced disease progression or withdrew consent. Participants had to wait 3 weeks from the last dose of ipilimumab in a parent study to the first dose of ipilimumab in the current study. |
| First reinduction: Ipilimumab, 3 to 10 mg/kg | EXPERIMENTAL | Participants who initially received ipilimumab, 3 mg/kg, in a parent study received ipilimumab, 10 mg/kg in the current study. Ipilimumab was administered as an individual open-label dose every 3 weeks for the first 10 weeks of reinduction for a total of 4 separate doses unless the patient experienced disease progression or withdrew consent. Participants had to wait 3 weeks from the last dose of ipilimumab in a parent study to the first dose of ipilimumab in the current study. |
| First reinduction: Ipilimumab, 10 to 10 mg/kg | EXPERIMENTAL | Participants who initially received ipilimumab, 10 mg/kg, in a parent study received ipilimumab, 10 mg/kg in the current study. Ipilimumab was administered as an individual open-label dose every 3 weeks for the first 10 weeks of reinduction for a total of 4 separate doses unless the patient experienced disease progression or withdrew consent. Participants had to wait 3 weeks from the last dose of ipilimumab in a parent study to the first dose of ipilimumab in the current study. |
| Extended maintenance: Ipilimumab, 0.3 mg/kg | EXPERIMENTAL | Participants who received ipilimumab, 0.3 mg/kg, in a parent study and who achieved extended clinical benefit received the same dose of ipilimumab (0.3 mg/kg) as maintenance in the current study. Maintenance dosing was administered every 12 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. |
| Extended maintenance: Ipilimumab, 3 mg/kg | EXPERIMENTAL | Participants who received ipilimumab, 3 mg/kg, in a parent study and who achieved extended clinical benefit received the same dose of ipilimumab (3 mg/kg) as maintenance in the current study. Maintenance dosing was administered every 12 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. |
| Extended maintenance: Ipilimumab, 10 mg | EXPERIMENTAL | Participants who received ipilimumab, 10 mg/kg, in a parent study and who achieved extended clinical benefit received the same dose of ipilimumab (10 mg/kg) as maintenance in the current study. Maintenance dosing was administered every 12 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. |
| Follow-up | NO_INTERVENTION | Participants did not receive any additional study treatment in current study but continued follow-up for the collection of survival data. |
| ipilimumab (MDX-010, BMS-734016) | EXPERIMENTAL | - |
| 1 | EXPERIMENTAL | - |
| 2 | EXPERIMENTAL | - |
| 3 | EXPERIMENTAL | - |
| A1 | ACTIVE_COMPARATOR | - |
| A2 | ACTIVE_COMPARATOR | - |
| Arm 1 | EXPERIMENTAL | - |
| Pts with Diffuse Large B Cell Lymphoma | EXPERIMENTAL | Patients with DLBCL not eligible for autologous stem cell transplant. All patients will receive dual checkpoint blocking antibody (DCBA) therapy of ipilimumab and nivolumab given at three week intervals, two times before, and two times following "immunotransplant" in which T cells (in whole PBMCs) are cryopreserved and re-infused (adoptive T cell transfer or ATCT) following lymphodepleting chemotherapy regimen, currently being employed in adoptive T cell therapies. |
| Cohort 1: Ipi + Nivo | EXPERIMENTAL | * Day 1: Ipilimumab 3 mg/kg i.v. * Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v. * Day 43: Nivolumab 3 mg/kg i.v. |
| Cohort 2a: high-Ipi + low-Nivo | EXPERIMENTAL | * Day 1: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v. * Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v. * Day 43: Nivolumab 3 mg/kg i.v. * Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection, day 56-84 |
| Cohort 2b: low-Ipi + high-Nivo | EXPERIMENTAL | * Day 1: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg i.v. * Days 22: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg i.v. * Day 43: Nivolumab 3 mg/kg i.v. * Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection, day 56-84 |
| EGFR patients with ipilimumab | EXPERIMENTAL | ipilimumab and erlotinib in EGFR mutated patients |
| ALK patients plus ipilimumab | EXPERIMENTAL | ipilimumab and crizotinib in ALK mutated patients |
| EGFR patients with nivolumab | EXPERIMENTAL | nivolumab and erlotinib in EGFR mutated patients |
| ALK patients plus nivolumab | EXPERIMENTAL | nivolumab and crizotinib in ALK mutated patients |
| Intratumoral Ipilimumab | EXPERIMENTAL | Patients receive a 3mg intratumoral injection of ipilimumab during a biopsy procedure. |
| Treatment: all patients | EXPERIMENTAL | Patients entering trial should be on stable dose of osi for ≥4 weeks. Patients will self-administer osi by mouth regardless of food once daily. Doses should be taken at about the same time every day (±6hrs) and recorded on the patient dosing diary. Doses missed outside of the dosing window should not be made up but patients should be instructed to take their next dose at their regularly scheduled time. Ipi will be administered at the assigned dose level every 21 days (±3days) for a max of 4 doses. Ipi must be infused using a volumetric pump over 90min (±10min) through an IV line. Upon completion of the ipilimumab regimen, patients will continue osimertinib daily until disease progression, initiation of new anti-cancer therapy, or death by any cause. |
| Neovax in Combination with Ipilimumab | EXPERIMENTAL | Patients will undergo surgery with the intent to resect the primary kidney tumor Neovax is a combination of Poly-ICLC and Neoantigen Peptides Priming doses of NeoVax will be administered on days 1, 4, 8, 15, and 22 * In the boost phase, vaccine will be administered on days 78 (week 12) and 134 (week 20 Ipilimumab will be injected within 1 cm of each NeoVax administration |
| NeoVax alone | EXPERIMENTAL | Patients will undergo surgery with the intent to resect the primary kidney tumor Neovax is a combination of Poly-ICLC and Neoantigen Peptides Priming doses of NeoVax will be administered on days 1, 4, 8, 15, and 22 * In the boost phase, vaccine will be administered on days 78 (week 12) and 134 (week 20) |
| A (VX15/2503, nivolumab, surgery) | EXPERIMENTAL | Participants receive VX15/2503 (pepinemab) IV over 60 minutes and nivolumab IV over 30 minutes on days 1 and 21 and undergo surgery between days 35-49. |
| B (VX15/2503, ipilimumab, surgery) | EXPERIMENTAL | Participants receive VX15/2503 (pepinemab) IV over 60 minutes and ipilimumab IV over 30 minutes on days 1 and 21 and undergo surgery between days 35-49. |
| C (VX15/2503, nivolumab, ipilimumab, surgery) | EXPERIMENTAL | Participants receive VX15/2503 (pepinemab) IV over 60 minutes, nivolumab IV over 30 minutes, and ipilimumab IV over 30 minutes on days 1 and 21 and undergo between days 35-49. |
| D (nivolumab, surgery) | EXPERIMENTAL | Participants receive nivolumab IV over 30 minutes on days 1 and 21 and undergo between days 35-49. |
| E (surgery) | ACTIVE_COMPARATOR | Participants undergo surgery. |
| Induction Phase:Ipilimumab | EXPERIMENTAL | Ipilimumab dose as specified |
| Maintenance Phase:Ipilimumab | EXPERIMENTAL | Ipilimumab dose as specified |
| Group 1 Liver: Concurrent (early) Ipilimumab and SBRT | EXPERIMENTAL | Participants with at least 1 liver metastasis - Treatment Group 1: Ipilimumab 3 mg/kg by vein on Day 1 of all 21 day cycles for a total of 4 doses. SBRT 50 Gy in 4 fractions to 1 - 4 liver lesion(s) on Days 1 - 4 of Cycle 1. |
| Group 2 Liver: Sequential (late) Ipilimumab and SBRT | EXPERIMENTAL | Participants with at least 1 liver metastasis - Treatment Group 2: Ipilimumab 3 mg/kg by vein on Day 1 of Cycles 1 and 2. After SBRT treatment, Ipilimumab given on Day 1 of Cycles 3 and 4. Each cycle is 21 days. SBRT 50 Gy in 4 fractions to 1 - 4 liver lesion(s) on Days 29 - 33 of each 21 day cycle. |
| Group 3 Lung: Concurrent (early) Ipilimumab and SBRT | EXPERIMENTAL | Participants with at least 1 lung metastasis - Treatment Group 3: Ipilimumab 3 mg/kg by vein on Day 1 of all 21 day cycles for a total of 4 doses. SBRT 50 Gy in 4 fractions to 1 - 4 lung lesion(s) on Days 1 - 4 of Cycle 1. |
| Group 4 Lung: Sequential (late) Ipilimumab and SBRT | EXPERIMENTAL | Participants with at least 1 lung metastasis - Treatment Group 4: Ipilimumab 3 mg/kg by vein on Day 1 of Cycles 1 and 2. After SBRT treatment, Ipilimumab given on Day 1 of Cycles 3 and 4. Each cycle is 21 days. SBRT 50 Gy in 4 fractions to 1 - 4 lung lesion(s) on Days 29 - 33 of each 21 day cycle. |
| Group 5 Liver/Lung Metastasis: (late) Ipilimumab and SBRT | EXPERIMENTAL | Participants with 1 liver or lung metastasis - Treatment Group 5: Ipilimumab 3 mg/kg by vein on Day 1 of Cycle 1. After SBRT treatment, Ipilimumab given on Day 1 of Cycles 2 - 4. Each cycle is 21 days. SBRT 60 Gy in 10 fractions to 1 - 4 lung, liver, or adrenal lesion (s) on Days 1 - 5 and Days 9 - 12 of Cycle 1. |
| Thyroid Expansion Cohort | EXPERIMENTAL | Participants enrolled in this arm treated to a total dose of 50 Gy in 4 fractions, 60 Gy in 10 fractions, or 20 Gy in 5 fractions with stereotactic radiotherapy to a liver or lung lesion. The choice of radiation dose will be at the discretion of the treating radiation oncologist. Participants receive Ipilimumab every 21 days for a total of 4 doses. |
| Ipilimumab + radiotherapy | EXPERIMENTAL | Patients receive ipilimumab (Ipi) 3mg/kg i.v. over 90 minutes, within 24 hours of starting radiotherapy (RT) to the biopsied lesion, 6 Gy x5, later changed to 9.5 Gy x3 (conformally or by intensity modulated RT (IMRT) with image guidance to maximally spare normal tissue). Ipilimumab is repeated on days 22, 43 (for patients who consent to the first biopsy), and 64. Repeat biopsy is performed between day 22-29, and patients are re-imaged between day 81-88 and evaluated for response (defined as an objective response by irRC of the measurable metastatic sites outside the radiation field). |
| Arm 1: Lirilumab + Ipilimumab | EXPERIMENTAL | Lirilumab and Ipilimumab on specific days |
| Dose Level 1: Ipilimumab, 3 mg/kg + Paclitaxel + Carboplatin | EXPERIMENTAL | Participants received ipilimumab, 3 mg/kg, administered as a single dose intravenously (IV) over 90 minutes every 3 weeks, plus paclitaxel, 175 mg/m\^2 , administered as a single dose IV over 3 hours every 3 weeks (up to 6 doses), and carboplatin, area under the curve (AUC)=6, administered as a single dose IV over 30-60 minutes every 3 weeks (up to 6 doses). |
| Dose Level 2: Ipilimumab, 10 mg/kg + Paclitaxel + Carboplatin | EXPERIMENTAL | Participants received ipilimumab, 10 mg/kg, administered as a single dose IV over 90 minutes every 3 weeks, plus paclitaxel, 175 mg/m\^2 , administered as a single dose IV over 3 hours every 3 weeks (up to 6 doses), and carboplatin, AUC=6, administered as a single dose IV over 30-60 minutes every 3 weeks (up to 6 doses). |
| Ipilimumab (Process B) | EXPERIMENTAL | Reference |
| Ipilimumab (Process C) | EXPERIMENTAL | Test |
| Arm C | ACTIVE_COMPARATOR | - |
| MDX-010 | EXPERIMENTAL | - |
| Arm 2 | EXPERIMENTAL | Specified dose on specified days |
| Name | Type | Description |
|---|---|---|
| Ipilimumab | BIOLOGICAL | Specified dose on specified days |
| Oxaliplatin | DRUG | Specified dose on specified days |
| Leucovorin | DRUG | Specified dose on specified days |
| Fluorouracil | DRUG | Specified dose on specified days |
| Irinotecan | DRUG | Specified dose on specified days |
| Bevacizumab | DRUG | Specified dose on specified days |
| Cetuximab | DRUG | Specified dose on specified days |
| Nivolumab | BIOLOGICAL | Specified dose on specified days |
| Carboplatin | DRUG | Specified dose on specified day |
| Paclitaxel | DRUG | Specified dose on specified day |
| Pemetrexed | DRUG | Specified dose on specified day |
| Cisplatin | DRUG | Specified dose on specified day |
| Dacarbazine | DRUG | - |
| Placebo matching Ipilimumab | OTHER | Specified dose on specified days |
| Placebo matching Nivolumab | OTHER | Specified dose on specified days |
| Placebo | OTHER | 0.9% sodium chloride injection, USP, or 5% dextrose injection |
| Etoposide | DRUG | - |
| Ipilimumab/ Nivolumab | DRUG | induction ipilimumab 1 mg/kg combined with nivolumab 3 mg/kg (I/N) every 3 weeks for cycles 1-4 followed by maintenance treatment with nivolumab 240mg every 2 weeks or 480mg every 4 weeks until disease progression |
| SBRT + Ipilimumab/Nivolumab | RADIATION | SBRT to the primary disease in-situ, prior to cycle 2-4 of I/N. Patients randomized to SBRT will undergo radiation planning during the first cycle of I/N to their primary kidney mass, and then the radiation will be delivered between cycles 1 and 2 to a dose of 30-40 Gy in 5 fractions every other day over 1.5 weeks. |
| Cryoablation | PROCEDURE | Cryoablation of the tumors occur between investigational agent treatment Cycles 1 and 2, and will be performed according to standard procedures |
| Ipilimumab + nivolumab | DRUG | Induction with immune checkpoint blockade: ipilimumab 3mg/kg on day 1, pilimumab 3mg/kg plus nivolumab 1mg/kg on day 22, and nivolumab 3mg/kg on day 43 Response evaluation after the last cycle of checkpoint inhibition. Chemoradiation will start 10-12 weeks after start of checkpoint inhibition according to the following scheme: * Mitoycine C (12mg/m2) on the first day of radiotherapy, followed by either 5-fluorouracil intravenously (500mg/m2) five days a week during week one and four of radiation, or oral capecitabin (2x825mg/m2) every day during the radiation period * Radiation with a preference for a four-week schedule, in which 55 Gy will be administered using intensity modulated radiation therapy |
| laboratory biomarker analysis | OTHER | Correlative studies |
| Ipilimumab 3mg/kg and nivolumab 1mg/kg | DRUG | Neoadjuvant for 2 doses on days 1 and 22 |
| Ipilimumab 1mg/kg Nivolumab 480mg and relatlimab 160mg | DRUG | Neoadjuvant for 2 doses at days 1 and 29 |
| Nivolumab 480mg and relatlimab 160mg | DRUG | Neoadjuvant for 2 doses on days 1 and 29 |
| Ipilimumab 1mg/kg and nivolumab 3mg/kg | DRUG | Neoadjuvant for 2 doses at days 1 and 22 |
| Pembrolizumab 200 mg | DRUG | Neoadjuvant for 2 doses at days 1 and 22 |
| SBRT | RADIATION | 1 fraction or 2 fractions delivered to the gross primary tumor and nodal disease, following the first treatment with ipilimumab + nivolumab on days 1-3. |
| Chemoradiotherapy | RADIATION | Capecitabine tablet with fractionated radiotherapy |
| UV1 vaccine + leukine | BIOLOGICAL | The mode of action of UV1 is to activate the immune system to induce T cells directed against telomerase (hTERT). UV1 vaccination amplifies the pool of hTERT specific tumor-reactive T cells from the naive repertoire and has the potential to increase the breadth and diversity of the tumor-reactive T cell response (epitope spreading). Vaccination with UV1 can thus provide the basis for increased efficacy of checkpoint inhibition therapy, by augmenting the pool of tumor specific T cells in patients with limited or insufficient numbers of T cell clones spontaneously primed by tumor antigens. Reciprocally, the efficacy of UV1 vaccination may be enhanced in combination with checkpoint inhibitors, since the clonal expansion and effector activity of UV1 induced T cells will otherwise be restricted by intrinsic immune regulatory and tumor induced suppressor mechanisms. |
| Stereotactic Radiotherapy | RADIATION | The first dose of immunotherapy Must be given prior to the start of radiotherapy. One fraction at between 16 to 22 Gy or 24 to 30 Gy hypofractionated for larger lesions. |
| Salvage therapy | OTHER | Any form of salvage therapy (surgery or radiotherapy) for intracranial disease progression, further disease control at any site, symptom control or treatment of cerebral haemorrhage or cerebral radionecrosis. |
| SipT Treatment | DRUG | All patients will receive standard of care SipT treatment every two weeks for a total of 3 treatments. The three treatments usually take about 30 days to complete. SipT treatment is given in three 1 hour infusions. Each SipT treatment is generated from a standard blood cell-collection procedure (called leukapheresis) performed 2-3 days prior to the infusion. |
| Cobimetinib | DRUG | Specified dose on specified days |
| Daratumumab | DRUG | Specified dose on specified days |
| BMS-986016 | DRUG | Specified dose on specified days |
| Vemurafenib | BIOLOGICAL | - |
| Best Supportive care (BSC) | OTHER | - |
| Gemcitabine | DRUG | Gemcitabine 1000 mg/m2 Days 1 \& 8 (all cycles) |
| Ipilimumab and Fotemustine | DRUG | Ipilimumab: 10 mg/kg q3 weeks for 4 doses, q12 weeks starting at Week 24 Fotemustine: 100 mg/m2 q1 week for 3 doses, q3 weeks starting at Week 9 |
| Corticosteroid: Betamethasone | DRUG | Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with betamethasone |
| Corticosteroid: Dexamethasone | DRUG | Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with dexamethasone |
| Corticosteroid: Fludrocortisone | DRUG | Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with fludrocortisone |
| Corticosteroid: Hydrocortisone | DRUG | Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with hydrocortisone |
| Corticosteroid: Meprednisone | DRUG | Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with meprednisone |
| Corticosteroid: Methylprednisolone | DRUG | Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with methylprednisolone |
| Corticosteroid: Prednisolone | DRUG | Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with prednisolone |
| Corticosteroid: Prednisone | DRUG | Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with prednisone |
| Corticosteroid: Triamcinolone | DRUG | Participants in the corticosteroid-dependent arm for whom adequate control of metastatic brain lesion-related neurologic signs and symptoms required concurrent corticosteroid therapy with triamcinolone |
| ipilimumab (MDX-010, BMS-734016) | DRUG | IV solution, IV, 10 mg/kg, Q 3 wks for 12 wks then Q 12 wks, 48+ weeks depending on response. |
| Ipilimumab+ Placebo | DRUG | Solution, Intravenous, 10 mg/kg, 3 weeks, 12 - 48 weeks depending on the response. |
| Ipilimumab+ Budesonide | DRUG | Solution/Capsule, Intravenous/Oral, 10 mg/kg + 9 mg, 3 weeks (Ipilimumab) + once daily until week 16 (Budesonide), 12 - 48 weeks depending on the response. |
| Tyrosinase/gp100/MART-1 Peptides | BIOLOGICAL | (All subjects in Part I and HLA-A\*0201 positive subjects only in Part II): SC, day 1 of wks 1,3,5,7,9,11,17, 21,25,33,41,53 Dose: 1 mg peptide emulsified in 1 mL Montanide ISA 51 VG.) |
| MDX-010 | DRUG | - |
| MDX-010 / MDX-010 + Docetaxel | DRUG | - |
| MDX-010 (CTLA-4) | DRUG | - |
| Erlotinib | DRUG | Erlotinib 150 mg once daily or current tolerable dose (given with Ipilimumab) |
| Crizotinib | DRUG | Crizotinib 250 mg twice daily or current tolerable dose (given with Ipilimumab) |
| Intratumoral Ipilimumab | DRUG | Patients with a planned resection of SCCHN will have a biopsy procedure 7-10 days prior to surgery and receive an injection of ipilimumab directly into a tumor. |
| Isolated hepatic perfusion | PROCEDURE | The procedure is performed under general anaesthesia. The caval vein is isolated infrahepatically above the renal veins and suprahepatically between the diaphragm and the pericardium. A catheter is placed in the retrohepatic portion of the caval vein for perfusion outflow. The portal vein is clamped and the proper hepatic artery is cannulated via the gastroduodenal artery. The liver perfusion is performed at a rate of 8- 9 ml/kg/min with a target liver temperature of 40 degrees Celsius. The leakage from the system was continuously recorded using Technetium labelled albumin (Vasculosis) injected into the perfusion circuit. Melphalan (1 mg/kg bodyweight divided into two doses, given 30 minutes apart) is added to the perfusion system. The perfusion is then continued for 60 minutes, after which the perfusion was discontinued. |
| Osimertinib | DRUG | Cohort 1: Osi 40 mg or 80 mg daily; Ipi 3 mg/kg every 3 weeks Cohort 2: Osi 40 mg or 80 mg daily; Ipi 1 mg/kg every 3 weeks |
| NeoVax | DRUG | combination of Neoantigen peptides and poly-ICLC |
| VX15/2503 | BIOLOGICAL | Given IV |
| Surgery | PROCEDURE | Undergo therapeutic conventional surgery |
| Stereotactic Body Radiation Therapy (SBRT) | RADIATION | Treatment Group 1 and 3: SBRT 50 Gy in 4 fractions to 1 - 4 liver lesion(s) on Days 1 - 4 of Cycle 1. Treatment Group 2 and 4: SBRT 50 Gy in 4 fractions to 1-4 liver lesion(s) on Days 29 - 33 of each 21 day cycle. Treatment Group 5: SBRT 60 Gy in 10 fractions to 1 - 4 lung, liver, or adrenal lesion (s) on Days 1 - 5 and Days 9 - 12 of Cycle 1. |
| Radiotherapy (IMRT or 3-D CRT) | RADIATION | - |
| Lirilumab | DRUG | - |
| Ipilimumab, 3 mg | DRUG | Intervenous (IV) injection, administered every 3 weeks for up to 6 cycles |
| Ipilimumab, 10 mg | DRUG | IV injection, administered every 3 weeks for up to 6 cycles |
Inclusion Criteria: * Histologically confirmed recurrent or metastatic colorectal cancer (CRC) irrespective of prior treatment history with chemotherapy and/or targeted agents not amenable to surgery (Applicable only during Part 1 enrollment of the study) * Histologically confirmed recurrent or met...
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MDX-010 is an investigational immunotherapy that has been studied in several cancer types and in HIV infection. Research has covered breast cancer, malignant melanoma, prostate cancer, and human immunodeficiency virus. It was developed by Bristol-Myers Squibb Company and reached Phase 2 testing in breast cancer.
MDX-010 has been studied for unresectable Stage III or Stage IV malignant melanoma, metastatic hormone-refractory prostate cancer, Stage IV breast cancer, and HIV infection. All of these programs are investigational, and the studies listed have been completed. It is not described as an approved treatment for any of these conditions.
MDX-010 is developed by Bristol-Myers Squibb Company, which trades on the New York Stock Exchange under the ticker BMY. The company sponsored the clinical studies of MDX-010 in melanoma, prostate cancer, breast cancer, and HIV.
MDX-010 has reached Phase 2, with a Phase 2 study conducted in Stage IV breast cancer. The melanoma, prostate cancer, and HIV studies were Phase 1. All listed trials are completed, and no active trials are ongoing. MDX-010 is investigational and has not been described as FDA approved.
Completed studies include NCT00083278 in Stage IV breast cancer, NCT00729950 in unresectable Stage III or Stage IV malignant melanoma, NCT00323882 in metastatic hormone-refractory prostate cancer, and NCT03407105, a dose-escalation study in people infected with HIV. All were conducted in the United States.