Phase 1 Safety and Tolerability of MEDI4736 in Combination With Dabrafenib and Trametinib or With Trametinib Alone

Browse trials for

• Melanoma 3,073
• Neoplasm Metastasis 3,562
• Parkinson Disease 4, Autosomal Dominant Lewy Body 156

Keywords

• Metastatic or Unresectable Melanoma, durvalumab (MEDI4736), dafrafenib, trametinib, BRAF-mutation positive, wild-type BRAF, PD-L1, PD-1

Melanoma

3,073 studies on the registry are indexed under Melanoma; 529 are open to participants now.

This study's enrollment of 68 is above the median of 38 across 2,400 interventional studies indexed under Melanoma.

Lead sponsor

MedImmune LLC is the lead sponsor of 270 studies on the registry; none are open to participants now.

Of its 52 completed or terminated interventional studies of FDA-regulated products, 29 (56%) have results posted.

First submitted after MedImmune LLC became part of AstraZeneca.

Study arms

• Experimental
  Cohort A1: Durvalumab (3 mg/kg) + Dabrafenib +Trametinib

  Participants will receive intravenous (IV) dose of 3 milligrams per kilogram (mg/kg) durvalumab every 2 weeks (Q2W) from Day 1 up to 12 months along with oral 150 mg dabrafenib capsule twice daily (BID) and oral 2 mg trametinib tablet once daily (QD) until confirmed disease progression (PD), initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 3 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.

  Biological: Durvalumab · Drug: Dabrafenib · Drug: Trametinib

• Experimental
  Cohort A2: Durvalumab (10 mg/kg) + Dabrafenib +Trametinib

  Participants will receive IV dose of 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral doses of dabrafenib 150 mg capsule BID and trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of dabrafenib and trametinib.

  Biological: Durvalumab · Drug: Dabrafenib · Drug: Trametinib

• Experimental
  Cohort B: Durvalumab (10 mg/kg) +Trametinib (Concurrent)

  Participants will receive concurrent doses of IV 10 mg/kg durvalumab Q2W from Day 1 up to 12 months along with oral dose of trametinib 2 mg tablet QD until confirmed PD, initiation of alternate cancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue treatment. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months and continued the treatment of trametinib.

  Biological: Durvalumab · Drug: Trametinib

• Experimental
  Cohort C: Durvalumab (10 mg/kg) +Trametinib (Sequential)

  Participants will receive sequential doses of oral trametinib tablet 2 mg QD from Day 1 to Day 42 and IV durvalumab 10 mg/kg Q2W starting from Day 29 (Week 5) up to 12 months. Post-durvalumab treatment period, participants who developed PD and meet the criteria for re-administration, will receive durvalumab 10 mg/kg up to an additional 12 months.

  Biological: Durvalumab · Drug: Trametinib

Interventions

• BiologicalDurvalumab

  Intravenous dose of 3 or 10 mg/kg durvalumab.

• DrugDabrafenib

  Oral dose of 150 mg dabrafenib capsule.

• DrugTrametinib

  Oral dose of 2 mg trametinib tablet.

Primary outcomes

1. Number of Participants With Dose Limiting Toxicities (DLTs)

   Dose limiting toxicities are defined as any Grade 3 or higher treatment-related (related to any study drug) toxicity that occurs during the DLT evaluation period. Number of participants with DLTs are reported.

   Time frame: From first dose of study drug (Day 1) until the planned 3rd dose of durvalumab (Day 29)

2. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

   An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. Serious adverse event is any AE that resulted in death, life threatening, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, is a congenital anomaly/birth defect in offspring of a study participant, is an important medical event that may jeopardize the participant or may require medical intervention. 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.

   Time frame: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

3. Number of Participants With Abnormal Vital Signs and Physical Examinations Reported as TEAEs

   Number of participants with abnormal vital signs and physical examinations reported as TEAEs are reported.

   Time frame: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

4. Number of Participants With Abnormal Clinical Laboratory Parameters Reported as TEAEs

   Number of participants with abnormal clinical laboratory parameters reported as TEAEs are reported.

   Time frame: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

5. Number of Participants With Abnormal Electrocardiograms (ECGs) and Echocardiograms (ECHOs) Reported as TEAEs

   Number of participants with abnormal electrocardiograms (ECGs) and echocardiograms (ECHOs) reported as TEAEs are reported.

   Time frame: From first dose of study drug (Day 1) up to 90 days after the last dose (up to 4.5 years)

Secondary outcomes

1. Percentage of Participants With Objective Response (OR)

   Objective Response is defined as confirmed complete response (CR) or confirmed partial response (PR) based on Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). A confirmed CR is defined as two CRs that were separated by at least 28 days. A confirmed PR is defined as two PRs or an un-confirmed PR and an un-confirmed CR that were separated by at least 28 days. A CR is defined as disappearance of all target and non-target lesions, normalization of tumor marker level and any pathological lymph nodes selected as target lesions must have a reduction in short axis to less than 10 mm. A PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

   Time frame: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

2. Duration of Response (DOR)

   Duration of response: Duration from first documentation of OR to first documented PD or death due to any cause, whichever occurs first. CR: disappearance of all target and non-target lesions, normalization of tumor marker level and any pathological lymph nodes selected as target lesions must have a reduction in short axis to less than 10 mm. PR: at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters. PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of \>= 5 mm, taking as reference smallest sum of diameters since treatment started including baseline sum of diameters.

   Time frame: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

3. Progression-free Survival (PFS)

   Progression-free Survival is defined as duration from the start of treatment with study drug until the first documented PD or death, whichever comes first. PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of \>= 5 mm, taking as reference smallest sum of diameters since treatment started including baseline sum of diameters. For participants who are alive and progression-free at the time of data cut-off for analysis, PFS was to be censored at the last tumor assessment date.

   Time frame: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

4. Overall Survival

   Overall survival (OS) is measured from the start of treatment until death. For participants who are alive at the end of study or lost to follow-up, OS was censored on the last date when participants are known to be alive.

   Time frame: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

5. Percentage of Participants With Disease Control

   Disease control is defined as confirmed CR or PR, or stable disease (SD) that was maintained for \>= 12 weeks based on RECIST v1.1. A confirmed CR is defined as two CRs that were separated by at least 28 days. A confirmed PR is defined as two PRs or an un-confirmed PR and an un-confirmed CR that were separated by at least 28 days. CR: disappearance of all target and non-target lesions, normalization of tumor marker level and any pathological lymph nodes selected as target lesions must have a reduction in short axis to less than 10 mm. A PR is defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. A SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of diameters while on study.

   Time frame: From the first dose of study drug until last participant completes 12 months of treatment (assessed up to 4.5 years)

6. Maximum Observed Plasma Concentration after First Dose (Cmax, 1st) of Durvalumab

   Maximum observed plasma concentration of durvalumab after first dose is reported.

   Time frame: Cohorts A and B: End of infusion on Day 1; Cohort C: End of infusion on Day 29

7. Maximum Observed Plasma Concentration at Steady State (Cmax, ss) of Durvalumab

   Maximum observed plasma concentration of durvalumab at steady state is reported.

   Time frame: Cohorts A and B: end of infusion on Day 141; Cohort C: end of infusion on Day 169

8. Trough Concentration at Steady State (Ctrough) of Durvalumab

   Trough concentration of durvalumab pre-dose at steady state is reported.

   Time frame: Cohorts A and B: Pre-dose on Day 141; Cohort C: Pre-dose on Day 169

9. Number of Participants With Postive Anti-Drug Antibodies (ADA) Titer to Durvalumab

   The number of participants with positive serum antibodies to durvalumab post dosing are reported.

   Time frame: Cohorts A and B: Days 1 and 29; Cohort C: Days 29 and 57

Publications

• Gordon MS, Lutzky J, Lawrence D, Butler M, Ascierto PA, Hug B, et al. Phase 1 study evaluating safety and tolerability of MEDI4736, an anti-programmed cell death ligand-1 (PD-L1) antibody, in combination with dabrafenib and trametinib or trametinib alone in patients with unresectable or metastatic melanoma. Ann Oncol 2014; 25(suppl_4): iv374-iv393 (abstract 8004).
• Ribas A, Butler M, Lutzky J, Lawrence DP, Robert C, Miller W, et al. Phase 1 study combining anti-PD-L1 (MEDI4736) and BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. J Clin Oncol 2015; 33 (15_suppl): (abstract 3003).
• Ribas A, Algazi A, Ascierto PA, Butler MO, Chandra S, Gordon M, Hernandez-Aya L, Lawrence D, Lutzky J, Miller WH Jr, Campbell KM, Delafont B, Marshall S, Mueller N, Robert C. PD-L1 blockade in combination with inhibition of MAPK oncogenic signaling in patients with advanced melanoma. Nat Commun. 2020 Dec 7;11(1):6262. doi: 10.1038/s41467-020-19810-w. PubMed 33288749 ↗