Brief Summary
This is a multicenter, open-label, dose-escalation, dose-exploration and dose-expansion study to evaluate the safety, tolerability, antitumor activity, pharmacokinetic (PK), pharmacodynamics, and immunogenicity of durvalumab (MEDI4736) in combination with monalizumab (IPH2201) in adult participants with selected advanced solid tumors and the combination of durvalumab and monalizumab (IPH2201) standard of care systemic therapy with or without biological agent and monalizumab (IPH2201) with biological agent administered to participants with recurrent or metastatic colorectal cancer (CRC).
Brief Title
A Study of Durvalumab (MEDI4736) and Monalizumab in Solid Tumors
Detailed Description
The study consists of 3 parts: dose escalation (Part 1), dose expansion (Part 2), and dose exploration (Part 3). Part 1 will evaluate dose escalation of durvalumab in combination with monalizumab in adult participants with select advanced solid tumor malignancies. Part 2 will evaluate further the identified dose of durvalumab in combination with monalizumab from Part 1 in adult participants with select advanced solid tumor malignancies. Part 3 will evaluate dose exploration of durvalumab in combination with monalizumab and standard of care systemic therapy with or without biological agent, and monalizumab in combination with biological agent in adult participants with CRC.
Categories
Completion Date
Completion Date Type
Estimated
Conditions
Advanced Solid Tumors
Eligibility Criteria
Inclusion Criteria:
1. Participants must have histologic documentation of advanced recurrent or metastatic cancer.
2. Participants must be at the recurrent/metastatic setting, with selected advanced solid tumors.
3. Participants must have at least one lesion that is measurable by RECIST v1.1
4. Part 3, Dose exploration, CRC participants can be treatment naïve but should not have received more than two line of systemic therapy in the recurrent/metastatic setting.
Exclusion Criteria
1. Prior treatment with immunotherapy agents. Prior treatment with antitumor vaccines may be permitted upon discussion with the medical monitor.
2. Prior participation in clinical studies that include durvalumab alone or in combination, where the study has registrational intent and the analyses for the primary endpoint have not yet been completed
3. Receipt of any conventional or investigational anticancer therapy within 4 weeks prior to the first dose of study treatment
4. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions is acceptable.
1. Participants must have histologic documentation of advanced recurrent or metastatic cancer.
2. Participants must be at the recurrent/metastatic setting, with selected advanced solid tumors.
3. Participants must have at least one lesion that is measurable by RECIST v1.1
4. Part 3, Dose exploration, CRC participants can be treatment naïve but should not have received more than two line of systemic therapy in the recurrent/metastatic setting.
Exclusion Criteria
1. Prior treatment with immunotherapy agents. Prior treatment with antitumor vaccines may be permitted upon discussion with the medical monitor.
2. Prior participation in clinical studies that include durvalumab alone or in combination, where the study has registrational intent and the analyses for the primary endpoint have not yet been completed
3. Receipt of any conventional or investigational anticancer therapy within 4 weeks prior to the first dose of study treatment
4. Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions is acceptable.
Inclusion Criteria
Inclusion Criteria:
1. Participants must have histologic documentation of advanced recurrent or metastatic cancer.
2. Participants must be at the recurrent/metastatic setting, with selected advanced solid tumors.
3. Participants must have at least one lesion that is measurable by RECIST v1.1
4. Part 3, Dose exploration, CRC participants can be treatment naïve but should not have received more than two line of systemic therapy in the recurrent/metastatic setting.
1. Participants must have histologic documentation of advanced recurrent or metastatic cancer.
2. Participants must be at the recurrent/metastatic setting, with selected advanced solid tumors.
3. Participants must have at least one lesion that is measurable by RECIST v1.1
4. Part 3, Dose exploration, CRC participants can be treatment naïve but should not have received more than two line of systemic therapy in the recurrent/metastatic setting.
Gender
All
Gender Based
false
Keywords
Colorectal, colon, CRC, solid tumors, check point inhibitors, immunotherapy, metastatic
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Actual
Last Update Submit Date
Maximum Age
99 Years
Minimum Age
18 Years
NCT Id
NCT02671435
Org Class
Industry
Org Full Name
MedImmune LLC
Org Study Id
D419NC00001
Overall Status
Active, not recruiting
Phases
Phase 1
Phase 2
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
A Phase 1/2 Study of Durvalumab and Monalizumab in Adult Subjects With Select Advanced Solid Tumors
Primary Outcomes
Outcome Description
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. Any TEAEs data is inclusive of both serious and other adverse events (non-serious).
Outcome Measure
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)
Outcome Time Frame
Day 1 through 246.9 weeks (maximum observed duration)
Outcome Description
Change from baseline in SBP and DBP (minimum post baseline change \[PBC\] and maximum PBC) are reported.
Outcome Measure
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)
Outcome Time Frame
Day 1 (baseline) through 246.9 weeks (maximum observed duration)
Outcome Description
Change from baseline in RR (minimum PBC and maximum PBC) are reported.
Outcome Measure
Change From Baseline in Respiratory Rate (RR)
Outcome Time Frame
Day 1 (baseline) through 246.9 weeks (maximum observed duration)
Outcome Description
Change from baseline in PR (minimum PBC and maximum PBC) are reported.
Outcome Measure
Change From Baseline in Pulse Rate (PR)
Outcome Time Frame
Day 1 (baseline) through 246.9 weeks (maximum observed duration)
Outcome Description
Change from baseline in BT (minimum PBC and maximum PBC) are reported.
Outcome Measure
Change From Baseline in Body Temperature (BT)
Outcome Time Frame
Day 1 (baseline) through 246.9 weeks (maximum observed duration)
Outcome Description
Change from baseline in OS (minimum PBC and maximum PBC) are reported.
Outcome Measure
Change From Baseline in Oxygen Saturation (OS)
Outcome Time Frame
Day 1 (baseline) through 246.9 weeks (maximum observed duration)
Outcome Description
Participants who had notable QTcF and QTcB interval change from baseline are reported.
Outcome Measure
Number of Participants With Notable Change in QTcF and QTcB From Baseline
Outcome Time Frame
Day 1 (baseline) through 246.9 weeks (maximum observed duration)
Outcome Description
Number of participants with at least 2-Grade shift from baseline in laboratory parameters are reported.
Outcome Measure
Number of Participants With at Least 2-Grade Shift From Baseline in Laboratory Parameters
Outcome Time Frame
Day 1 (baseline) through 246.9 weeks (maximum observed duration)
Outcome Description
DLT: Any study drug related Grade (G) 3 or higher toxicity that occurred during DLT evaluation period including: any G\>=3 noninfectious colitis/pneumonitis, liver transaminase elevation (TE) \>=5 but =\<8 upper limit of normal (ULN), any G4 immune-mediated AE (imAE)/immune-related AE (irAE), any G\>=3 clinically significant non-hematologic toxicity, TE \>8 ULN or total bilirubin (TBL) \>5 ULN, increase in AST or ALT \>=3 ULN along with TBL \>=2 ULN, thrombocytopenia (G3/4 associated with G3/higher hemorrhage, G3 that did not improve by at least 1 grade within 7 days, and G4), G4 febrile neutropenia (FN), G3 FN of \>=5 days and G3 FN regardless of duration, G4 neutropenia of \>7 days, G3/4 neutropenia not associated with fever/systemic infection, and anemia (G3 and G4).
Outcome Measure
Number of Participants With Dose Limiting Toxicities (DLTs)
Outcome Time Frame
From Day 1 to 28 days after the first dose of study drugs
Outcome Description
The OR is defined as best overall response of confirmed complete response (CR) or confirmed partial response (PR) according to Response Evaluation Criteria in Solid Tumours Version 1.1 (RECIST V 1.1) guidelines. The CR is defined as disappearance of all target and non-target lesions and normalization of tumor marker level lesions. The PR is defined as at least a 30% decrease in the sum of the diameters of target lesions (compared to baseline) and no new nontarget lesion. A confirmed PR is defined as two PRs or an un-confirmed PR and an unconfirmed CR that were separated by at least 28 days with no evidence of progression in between.
Outcome Measure
Percentage of Participants With Objective Response (OR) in Exploration Cohorts C1A and C1B
Outcome Time Frame
Baseline (Days -28 to -1) through 54.8 months (maximum observed duration)
Secondary Ids
Secondary Id
D419NC00001
Secondary Id
2016-000662-38
Secondary Outcomes
Outcome Description
The OR is defined as best overall response of CR or confirmed PR according to RECIST V 1.1 guidelines. The CR is defined as disappearance of all target and non-target lesions and normalization of tumor marker level lesions. The PR is defined as at least a 30% decrease in the sum of the diameters of target lesions (compared to baseline) and no new nontarget lesion. A confirmed PR is defined as two PRs or an un-confirmed PR and an unconfirmed CR that were separated by at least 28 days with no evidence of progression in between.
Outcome Time Frame
Baseline (Days -28 to -1) through 54.8 months (maximum observed duration)
Outcome Measure
Percentage of Participants With OR
Outcome Description
The OR is defined as best overall response of confirmed CR or confirmed PR according to RECIST V 1.1 guidelines. The CR is defined as disappearance of all target and non-target lesions and normalization of tumor marker level lesions. The PR is defined as at least a 30% decrease in the sum of the diameters of target lesions (compared to baseline) and no new nontarget lesion. A confirmed PR is defined as two PRs or an un-confirmed PR and an unconfirmed CR that were separated by at least 28 days with no evidence of progression in between.
Outcome Time Frame
Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)
Outcome Measure
Percentage of Participants With OR in Exploration Cohorts C2A and C2B
Outcome Description
The DC is defined as best overall response of confirmed CR, confirmed PR, or stable disease (SD) based on RECIST v1.1. The CR is defined as disappearance of all target and non-target lesions and normalization of tumor marker level lesions. The PR is defined as at least a 30% decrease in the sum of the diameters of target lesions (compared to baseline) and no new nontarget lesion. A confirmed PR is defined as two PRs or an un-confirmed PR and an unconfirmed CR that were separated by at least 28 days with no evidence of progression in between. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. Participants with SD were included in the DC if they maintained SD for \>= 8 weeks from start of treatment. The DCR16 and DCR24 are reported (participants with SD \>= 16 weeks and \>=24 weeks).
Outcome Time Frame
Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)
Outcome Measure
Percentage of Participants With Disease Control (DC)
Outcome Description
The DC is defined as best overall response of confirmed CR, confirmed PR, or SD based on RECIST v1.1. The CR is defined as disappearance of all target and non-target lesions and normalization of tumor marker level lesions. The PR is defined as at least a 30% decrease in the sum of the diameters of target lesions (compared to baseline) and no new nontarget lesion. A confirmed PR is defined as two PRs or an un-confirmed PR and an unconfirmed CR that were separated by at least 28 days with no evidence of progression in between. The SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. Participants with SD were included in the DC if they maintained SD for \>= 8 weeks from start of treatment. The DCR16 and DCR24 are reported (participants with SD \>= 16 weeks and \>=24 weeks).
Outcome Time Frame
Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)
Outcome Measure
Percentage of Participants With DC in Exploration Cohorts (C1A, C1B, C2A, and C2B)
Outcome Description
The DoR is defined as the duration from the first documentation of OR (confirmed CR or confirmed PR) to the first documented disease progression (PD) based on RECIST v1.1 or death due to any cause, whichever occurred first. The CR is defined as disappearance of all target and non-target lesions and normalization of tumor marker level lesions. The PR is defined as at least a 30% decrease in the sum of the diameters of target lesions (compared to baseline) and no new nontarget lesion. A confirmed PR is defined as two PRs or an un-confirmed PR and an unconfirmed CR that were separated by at least 28 days with no evidence of progression in between. The PD is defined as at least a 20% increase in the sum of diameters of target lesions or unequivocal progression of existing non-target lesions, taking as reference the smallest sum on study and appearance of one or more new lesions. The DoR was evaluated using Kaplan-Meier method.
Outcome Time Frame
Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)
Outcome Measure
Duration of Response (DoR)
Outcome Description
The DoR is defined as the duration from the first documentation of OR (confirmed CR or confirmed PR) to the first documented PD based on RECIST v1.1 or death due to any cause, whichever occurred first. The CR is defined as disappearance of all target and non-target lesions and normalization of tumor marker level lesions. The PR is defined as at least a 30% decrease in the sum of the diameters of target lesions (compared to baseline) and no new nontarget lesion. A confirmed PR is defined as two PRs or an un-confirmed PR and an unconfirmed CR that were separated by at least 28 days with no evidence of progression in between. The PD is defined as at least a 20% increase in the sum of diameters of target lesions or unequivocal progression of existing non-target lesions, taking as reference the smallest sum on study and appearance of one or more new lesions. The DoR was evaluated using Kaplan-Meier method.
Outcome Time Frame
Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)
Outcome Measure
DoR in Exploration Cohorts (C1A, C1B, C2A, and C2B)
Outcome Description
The PFS is defined as the time from the start of study treatment until the first documentation of PD based on RECIST v1.1 or death due to any cause, whichever occurred first. The PD is defined as at least a 20% increase in the sum of diameters of target lesions or unequivocal progression of existing non-target lesions, taking as reference the smallest sum on study and appearance of one or more new lesions. The PFS was estimated using Kaplan-Meier method.
Outcome Time Frame
Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)
Outcome Measure
Progression-Free Survival (PFS)
Outcome Description
The PFS is defined as the time from the start of study treatment until the first documentation of PD based on RECIST v1.1 or death due to any cause, whichever occurred first. The PD is defined as at least a 20% increase in the sum of diameters of target lesions or unequivocal progression of existing non-target lesions, taking as reference the smallest sum on study and appearance of one or more new lesions. The PFS was estimated using Kaplan-Meier method.
Outcome Time Frame
Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)
Outcome Measure
Progression-Free Survival (PFS) in Exploration Cohorts (C1A, C1B, C2A, and C2B)
Outcome Description
The overall survival is defined as the time from the start of study treatment until death due to any cause. The overall survival was estimated using Kaplan-Meier method.
Outcome Time Frame
Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)
Outcome Measure
Overall Survival
Outcome Description
The overall survival is defined as the time from the start of study treatment until death due to any cause. The overall survival was estimated using Kaplan-Meier method.
Outcome Time Frame
Baseline (-28 to -1 day) through 54.8 weeks (maximum observed duration)
Outcome Measure
Overall Survival in Exploration Cohorts (C1A, C1B, C2A, and C2B)
Outcome Description
Serum Cmax of monalizumab at pre-dose and end of infusion are reported.
Outcome Time Frame
Day 85: Pre-dose and end of infusion (within 10 minutes) after cohort specific infusions
Outcome Measure
Maximum Observed Serum Concentration (Cmax) of Monalizumab
Outcome Description
Serum Cmin of monalizumab at pre-dose and end of infusion are reported.
Outcome Time Frame
Day 85: Pre-dose and end of infusion (within 10 minutes) after cohort specific infusions
Outcome Measure
Minimum Observed Serum Concentration (Cmin) of Monalizumab
Outcome Description
Serum concentration of durvalumab is reported.
Outcome Time Frame
Pre-dose (PRE) on Day 1 of Weeks 1, 5, 9, 13, and 25 and post-dose (POST) on Day 1 of Weeks 1 and 13
Outcome Measure
Serum Concentration of Durvalumab
Outcome Description
Serum concentration of cetuximab is reported.
Outcome Time Frame
Pre-dose (PRE) on Day 1 of Weeks 1, 5, 9, and 13 and post-dose (POST) on Day 1 of Weeks 1, 5, and 13
Outcome Measure
Serum Concentration of Cetuximab
Outcome Description
Number of participants with positive ADA to monalizumab are reported. Persistent positive is defined as positive at \>= 2 post-baseline assessments (with \>=16 weeks between first and last positive) or positive at last post-baseline assessment. Transient positive is defined as negative at last post-baseline assessment and positive at only one post-baseline assessment or at \>= 2 post-baseline assessments (with \<16 weeks between first and last positive). Treatment-boosted ADA is defined as baseline ADA titer that was boosted to a 4-fold or higher level following drug administration. Treatment-emergent ADA is defined as the sum of treatment-induced ADA (post-baseline positive only) and treatment-boosted ADA.
Outcome Time Frame
Day 1 through 54.8 months (Day 1 of Weeks 1, 5, 13, and 25, and 90 days after the last dose of monalizumab)
Outcome Measure
Number of Participants With Positive Anti-Drug Antibodies (ADA) to Monalizumab
Outcome Description
Number of participants with positive ADA to monalizumab are reported. Persistent positive is defined as positive at \>= 2 post-baseline assessments (with \>= 16 weeks between first and last positive) or positive at last post-baseline assessment. Transient positive is defined as negative at last post-baseline assessment and positive at only one post-baseline assessment or at \>= 2 post-baseline assessments (with \<16 weeks between first and last positive). Treatment-boosted ADA is defined as baseline ADA titer that was boosted to a 4-fold or higher level following drug administration. Treatment-emergent ADA is defined as the sum of treatment-induced ADA (post-baseline positive only) and treatment-boosted ADA.
Outcome Time Frame
Day 1 through 54.8 months (Day 1 of Weeks 1, 5, 13, and 25, and 90 days after the last dose of monalizumab)
Outcome Measure
Number of Participants With Positive ADA to Durvalumab
Outcome Description
Number of participants with positive ADA to cetuximab are reported. Persistent positive is defined as positive at \>= 2 post-baseline assessments (with \>=16 weeks between first and last positive) or positive at last post-baseline assessment. Transient positive is defined as negative at last post-baseline assessment and positive at only one post-baseline assessment or at \>= 2 post-baseline assessments (with \<16 weeks between first and last positive). Treatment-boosted ADA is defined as baseline ADA titer that was boosted to a 4-fold or higher level following drug administration. Treatment-emergent ADA is defined as the sum of treatment-induced ADA (post-baseline positive only) and treatment-boosted ADA.
Outcome Time Frame
Day 1 through 54.8 months (Day 1 of Weeks 1, 5, 9 [if EOT occurred], and 13, and 30 days after the last dose of monalizumab)
Outcome Measure
Number of Participants With Positive ADA to Cetuximab
Outcome Description
Number of participants with PD-L1 expression in pre-treatment tumor biopsies is reported. The participants were stratified into four categories: tumor cells (TC) \>= 25%, TC\<25%, TC\>=1%, and TC\<1%, based on the historical use of PD-L1 cutoffs.
Outcome Time Frame
Screening (Days -28 to -1)
Outcome Measure
Number of Participants With Programmed Death Ligand 1 (PD-L1) Expression in Pretreatment Tumor Biopsies
Outcome Description
The HLA-E expression in pre-treatment tumor biopsies is reported.
Outcome Time Frame
Screening (Days -28 to -1)
Outcome Measure
Number of Participants With Human Leukocyte Antigen (HLA)-E Expression in Pretreatment Tumor Biopsies
See Also Links
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Estimated
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
99
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Sanjay Goel
Investigator Email
sgoel@montefiore.org
Investigator Phone
718-405-8404