Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Tremelimumab · 10 trials · 9 indications
OS is defined as the time from randomisation until the date of death due to any cause.
PFS is defined as time from randomization until progression per RECIST 1.1 as assessed by BICR or death due to any cause
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) \>= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. ORR is defined as the proportion of all subjects with confirmed PR or CR according to RECIST 1.1.
ORR will include confirmed complete response (CR) + confirmed partial response (PR) and will be determined as per RECIST version 1.1. A confirmed response is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 4 weeks apart.
Time from randomization to death from any cause with patients who were alive at the time of the final analysis or who became lost to follow-up censored at their last date known to be alive.
A DLT was defined as treatment-related toxicity that occurred during DLT evaluation period including: any Grade 4 immune-related adverse event (irAE), any Grade 3 colitis or any Grade 3 noninfectious pneumonitis irrespective of duration, any \>= Grade 2 pneumonitis that does not resolve to \<= Grade 1 within 7 days of initiation of maximal supportive care, any other Grade 3 irAE (excluding colitis or pneumonitis) that does not downgrade to Grade 2 within 7 days after onset of the event despite optimal medical management including systemic corticosteroids or does not downgrade to \<= Grade 1 or baseline within 14 days, liver transaminase elevation \> 8 × upper limit of normal (ULN) or total bilirubin \> 5 × ULN, aspartate aminotransferase or alanine aminotransferase \> 3 × ULN with concurrent increase in total bilirubin \> 2 × ULN without evidence of cholestasis or alternative explanations, and any \>= Grade 3 non-irAE (except for the protocol stated conditions).
An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. The TEAEs are defined as events present at baseline that worsened in intensity after administration of study drug or events absent at baseline that emerged after administration of study drug. There will be no updated results for this outcome measure at the time of end of study.
Participants with clinically important Common Terminology Criteria for Adverse Events (CTCAE) grade changes to 3 or 4 in hematology and chemistry parameters are reported. There will be no updated results for this outcome measure at the time of end of study.
Vital sign assessment included pulse rate, blood pressure, temperature, weight, and respiratory rate. Vital signs abnormalities recorded as TEAEs are reported. There will be no updated results for this outcome measure at the time of end of study.
Number of participants with ECG abnormalities recorded as TEAEs are reported. There will be no updated results for this outcome measure at the time of end of study.
Overall survival (OS) by treatment arm
Determine the recommended phase 2 dose (RP2D) from BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) patients treated with each of the following immunotherapy study regimens: Durvalumab (cohort 1) Durvalumab + intravesical BCG (cohort 2) Durvalumab + radiation (cohort 3) Durvalumab + intravesical Gemcitabine + intravesical Docetaxel (cohort 4) Durvalumab + Tremelimumab + intravesical Gemcitabine + intravesical Docetaxel (cohort 5) Intravesical NAI + intravesical Gemcitabine (cohort 6) Intravesical NAI + intravesical Gemcitabine + intravesical Docetaxel (cohort 7) Subcutaneous NAI + intravesical NAI + intravesical Gemcitabine + intravesical Docetaxel (cohort 8) The RP2D of each immunotherapy study arm is defined as the dose level at which \< 2 out of 6, \< 4 out of 9, or \< 5 out of 12 patients enrolled within an individual study arm experience dose-limiting toxicity.
The complete response rate within each study arm is defined as the proportion of patients within each arm that demonstrate no evidence of recurrent or persistent high grade urothelial carcinoma of the bladder of any stage at any post-treatment disease assessment.
To investigate the safety and tolerability of tremelimumab and/ or MEDI4736 when given to Japanese patients
The primary objective of this phase 1 study is to determine the safety and tolerability of oral Gefitinib in combination with three escalating doses of Tremelimumab and to establish a recommended phase 2 dose. Overall safety profile will be characterized by type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events \[NCICTCAE\] Version 4.03), timing of adverse events and laboratory abnormalities in the first and in the following cycles
| Arm | Type | Description |
|---|---|---|
| Arm A | EXPERIMENTAL | Tremelimumab , rilvegostomig and bevacizumab |
| Arm B | EXPERIMENTAL | Rilvegostomig, and bevacizumab |
| Arm C | ACTIVE_COMPARATOR | Atezolizumab, and bevacizumab |
| Tremelimumab | EXPERIMENTAL | Tremelimumab 750 mg IV Day 1 of each 28 day cycle. Up to 7 cycles. |
| Single Tremelimumab with Regular Interval Durvalumab plus Gemcitabine and Cisplatin | EXPERIMENTAL | Cycles 1 through 8 will be in 3-week intervals and Cycles 9+ will be in 4-week intervals. Tremelimumab is administered at 300mg intravenously once at Cycle 1. Durvalumab is administered at 1500mg intravenously every 3 weeks for Cycles 1-8, then every 4 weeks for Cycles 9+. Gemcitabine is administered at 1000mg/m\^2 intravenously on Day 1 and Day 8 of Cycles 1-8 only. Cisplatin is administered at 25mg/m\^2 intravenously on Day 1 and Day 8 of Cycles 1-8 only. |
| Best Supportive Care | ACTIVE_COMPARATOR | Best supportive care available |
| Durvalumab plus Tremelimumab and Best Supportive Care | EXPERIMENTAL | Tremelimumab 75mg IV 60 minutes Day 1, cycles 1-4 Durvalumab 1500mg IV 60 minutes Day 1 every 28 days. Plus best supportive care |
| Part 1: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg | EXPERIMENTAL | Participants in Part 1A (safety run-in cohort) and Part 1 B (efficacy-gating cohort) will receive tremelimumab 1 mg/kg every 4 weeks (Q4W) 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first. |
| Parts 2 and 3: Durvalumab 1500 mg | EXPERIMENTAL | Participants will receive durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first. |
| Parts 2 and 3: Tremelimumab 300 mg + Durvalumab 1500 mg | EXPERIMENTAL | Participants will receive tremelimumab 300 mg 1 dose and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow, or development of other reason for treatment discontinuation, whichever occurs first. |
| Parts 2 and 3: Tremelimumab 750 mg | EXPERIMENTAL | Participants will receive tremelimumab 750 mg Q4W 7 doses followed by every 12 weeks (Q12W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first. |
| Parts 2 and 3: Tremelimumab 75 mg + Durvalumab 1500 mg | EXPERIMENTAL | Participants will receive tremelimumab 75 mg Q4W 4 doses and durvalumab 1500 mg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first. Participant recruitment to this arm was closed following protocol amendment 5. |
| Part 4: Durvalumab 1120 mg + Bevacizumab 15 mg/kg | EXPERIMENTAL | Participants will receive durvalumab 1120 mg and bevacizumab 15 mg/kg every 3 weeks (Q3W) until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first |
| China Cohort: Durvalumab 20 mg/kg | EXPERIMENTAL | Participants will receive durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first. |
| China Cohort: Tremelimumab 10 mg/kg | EXPERIMENTAL | Participants will receive tremelimumab 10 mg/kg Q4W 7 doses followed by Q12W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first. |
| China Cohort: Tremelimumab 1 mg/kg + Durvalumab 20 mg/kg | EXPERIMENTAL | Participants will receive tremelimumab 1 mg/kg Q4W 4 doses and durvalumab 20 mg/kg Q4W until confirmed progressive disease, withdrawal of consent, lost to follow-up, or development of other reason for treatment discontinuation, whichever occurs first. |
| Placebo | PLACEBO_COMPARATOR | Placebo |
| Phase 1: Cohort 1 | EXPERIMENTAL | Durvalumab monotherapy |
| Phase 1: Cohort 2 | EXPERIMENTAL | Durvalumab plus BCG |
| Phase 1: Cohort 3 | EXPERIMENTAL | Durvalumab plus External Beam Radiotherapy (EBRT) (BCG re-treatment) - Cross-over to Durvalumab Monotherapy |
| Phase 1: Cohort 4 | EXPERIMENTAL | Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments. |
| Phase 1: Cohort 5 | EXPERIMENTAL | NOTE: Cohort 5 was abandoned prior to any patients enrolled. Durvalumab + Tremelimumab + Gem/Doc The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments. For the intravenous medications, durvalumab should be administered first followed by tremelimumab. |
| Phase 1: Cohort 6 | EXPERIMENTAL | Intravesical NAI plus Gemcitabine |
| Phase 2: Cohort 4 Expansion | EXPERIMENTAL | Durvalumab + Gemcitabine/Intravesical Docetaxel (Gem/Doc) The sequence of administration is flexible to allow for scheduling of both the infusion and intravesical treatments. |
| Phase 1: Cohort 7 | EXPERIMENTAL | Intravesical NAI plus Gemcitabine and Docetaxel |
| Phase 1: Cohort 8 | EXPERIMENTAL | Subcutaneous NAI plus Intravesical NAI plus Gemcitabine and Docetaxel |
| Phase 1: Cohort 9 | EXPERIMENTAL | Additional Regimens TBD |
| Part A | OTHER | Dose escalation of tremelimumab mono therapy for advanced solid malignancies |
| Part B | OTHER | Combination therapy of tremelimumab and MEDI4736 for advanced solid malignancies |
| Part C | OTHER | Fixed dose of tremelimumab for malignant mesothelioma |
| Treatment | EXPERIMENTAL | * Cohort 1: Tremelimumab 3 mg/kg every 4 Weeks plus Gefitinib 250 mg/daily, 6 patients (+ 6 patients if 3 mg/kg is the MTD) * Cohort 2: Tremelimumab 6 mg/kg every 4 Weeks plus Gefitinib 250 mg/daily, 6 patients (+ 6 patients if 6 mg/kg is the MTD) * Cohort 3: Tremelimumab 10 mg/kg every 4 Weeks plus Gefitinib 250 mg/daily, 6 patients (+ 6 patients if 10 mg/kg is the MTD) |
| Name | Type | Description |
|---|---|---|
| Tremelimumab | DRUG | IV therapy |
| Rilvegostomig | DRUG | IV therapy |
| Bevacizumab | DRUG | IV therapy |
| Atezolizumab | DRUG | IV therapy |
| Durvalumab | DRUG | Durvalumab IV (intravenous) |
| Transarterial Chemoembolization (TACE) | PROCEDURE | TACE (chemo and embolic agent injection into the hepatic artery) |
| Lenvatinib | DRUG | Lenvatinib (oral) |
| Gemcitabine | DRUG | Gemcitabine is administered at 1000mg/m\^2 intravenously on Day 1 and Day 8 of Cycles 1-8 only. |
| Cisplatin | DRUG | Cisplatin is administered at 25mg/m\^2 intravenously on Day 1 and Day 8 of Cycles 1-8 only. |
| Best Supportive Care | OTHER | - |
| Placebo | DRUG | Placebo is to be administered as an IV solution, followed by observation. |
| Durvalumab (Cohort 1-3) | DRUG | Durvalumab 1120 mg intravenously Day 1 every 21 days x 8 cycles. |
| External Beam Radiotherapy (EBRT) | RADIATION | EBRT 6 Gy x 3; Cycle 1 Day 1, 3, and 5 |
| Bacillus Calmette-Guérin (BCG) | BIOLOGICAL | Dose level 0 (starting dose) = Full-dose Dose level-1 = 1/3rd-dose BCG. Dose level -1 is expected to be utilized during the phase II portion of the study due to the ongoing and persistent shortage of BCG in the US. |
| Docetaxel | DRUG | Docetaxel 37.5 mg intravesical weekly (+/- 2 days) x 6 doses. |
| Durvalumab (Cohort 4/5) | DRUG | Durvalumab 1500 mg intravenously Day 1 (+/- 2 days) every 28 days x 6 cycles. |
| To be determined | OTHER | Other regimens to be determined |
| Intravesical NAI (Cohorts 6-7) | DRUG | For all cohorts containing intravesical NAI treatment, starting in Week 1, induction intravesical NAI 400 ug will be administered weekly x 6 doses via a foley catheter into an empty bladder and maintained in the bladder for 60 minutes. |
| Subcutaneous NAI (Cohort 8) | DRUG | For all cohorts containing subcutaneous NAI treatment, starting in Week 1, NAI 10 ug/kg will be administered biweekly for 3 doses via subcutaneous injection. |
| MEDI4736 | DRUG | MEDI4736 administered intravenously. |
| Gefitinib | DRUG | Oral tablet |
Inclusion Criteria: * Locally advanced or metastatic and/or unresectable HCC * WHO/ECOG performance status of 0 or 1 * BCLC stage B (that is not eligible for locoregional therapy) or stage C. * Child-Pugh Score class A * At least one measurable target lesion * Participants with active HBV infection...