Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Ipilimumab · 44 trials · 51 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.
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.
OS is defined for each participant as the time between randomization date and death due to any cause. The survival time for participants who had not died was censored at the last known alive date. Median and associated 2-sided 95% confidence intervals were calculated using the method of Brookmeyer and Crowley.
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.
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)
Percentage of patients alive at 1-year from first dose of treatment.
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%.
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).
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.
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.
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.
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.
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.
| 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 |
| 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 | - |
| 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. |
| 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 (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. |
| 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) |
| 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 |
| Nivolumab Monotherapy | EXPERIMENTAL | - |
| Nivolumab + Ipilimumab | 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 |
| 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. |
| 1 | EXPERIMENTAL | - |
| 2 | EXPERIMENTAL | - |
| 3 | EXPERIMENTAL | - |
| ipilimumab (MDX-010, BMS-734016) | EXPERIMENTAL | - |
| 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. |
| 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. |
| 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 |
| Ipilimumab (Process B) | EXPERIMENTAL | Reference |
| Ipilimumab (Process C) | EXPERIMENTAL | Test |
| Arm A | ACTIVE_COMPARATOR | - |
| Arm B | ACTIVE_COMPARATOR | - |
| Arm C | ACTIVE_COMPARATOR | - |
| A1 | ACTIVE_COMPARATOR | - |
| A2 | ACTIVE_COMPARATOR | - |
| 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 |
| Dacarbazine | DRUG | - |
| Placebo matching Ipilimumab | OTHER | Specified dose on specified days |
| Placebo matching Nivolumab | OTHER | Specified dose on specified days |
| Paclitaxel | BIOLOGICAL | - |
| Carboplatin | BIOLOGICAL | - |
| Placebo | OTHER | 0.9% sodium chloride injection, USP, or 5% dextrose injection |
| Etoposide | DRUG | - |
| Cisplatin | DRUG | - |
| Cryoablation | PROCEDURE | Cryoablation of the tumors occur between investigational agent treatment Cycles 1 and 2, and will be performed according to standard procedures |
| laboratory biomarker analysis | OTHER | Correlative studies |
| 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 |
| 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 | - |
| 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, 0.3mg/kg, Q 3 wks for 12 wks then Q 12 wks, 48+ weeks depending on 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.) |
| 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 |
| VX15/2503 | BIOLOGICAL | Given IV |
| Surgery | PROCEDURE | Undergo therapeutic conventional surgery |
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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