A Study of Durvalumab (MEDI4736) and Monalizumab in Solid Tumors

Phase 1

Active, not recruiting

Conditions: Advanced Solid Tumors

Interventions: Drug: Monalizumab
Drug: Durvalumab
Drug: mFOLFOX6
Drug: Cetuximab
Drug: Bevacizumab

Registration Number: NCT02671435

Lead Sponsor: MedImmune LLC

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).

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.

Recruitment & Eligibility

Status: ACTIVE_NOT_RECRUITING

Sex: All

Target Recruitment: 383

Inclusion Criteria

Participants must have histologic documentation of advanced recurrent or metastatic cancer.
Participants must be at the recurrent/metastatic setting, with selected advanced solid tumors.
Participants must have at least one lesion that is measurable by RECIST v1.1
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

Prior treatment with immunotherapy agents. Prior treatment with antitumor vaccines may be permitted upon discussion with the medical monitor.
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
Receipt of any conventional or investigational anticancer therapy within 4 weeks prior to the first dose of study treatment
Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions is acceptable.

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dose-expansion Cohort: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W (MSS-CRC)	Durvalumab	Participants with microsatellite-stable colorectal cancer (MSS-CRC) will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-escalation Cohort 1: Monalizumab 22.5 mg Q2W + Durvalumab 1500 mg Q4W	Monalizumab	Participants will receive intravenous (IV) infusions of durvalumab 1500 mg every 4 weeks (Q4W) in combination with monalizumab 22.5 mg every 2 weeks (Q2W) up to 3 years until unacceptable toxicity, documentation of confirmed disease progression (PD), or documentation of subject withdrawal for another reason.
Dose-escalation Cohort 3: Monalizumab 225 mg Q2W + Durvalumab 1500 mg Q4W	Durvalumab	Participants will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 225 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-escalation Cohort 5: Monalizumab 750 mg Q4W + Durvalumab 1500 mg Q4W	Durvalumab	Participants will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q4W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-expansion Cohort: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W (ovarian)	Durvalumab	Participants with ovarian cancer will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort A1: Monalizumab 750 mg Q2W+Durvalumab 1500 mg Q4W+mFOLFOX6 Q2W+Bevacizumab Q2W	mFOLFOX6	Participants with first-line (1L) MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W plus mFOLFOX (oxaliplatin 85 mg/m\^2 IV infusion, folinic acid 400 mg/m\^2 infusion, fluorouracil 400 mg/m\^2 IV bolus, followed by 2400 mg/m\^2 continuous IV infusion over 46 to 48 hours on Day 1) Q2W plus IV infusion of bevacizumab 5 mg/kg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration CohortA2: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W + mFOLFOX6 Q2W + Cetuximab Q2W	mFOLFOX6	Participants with 1L MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W, plus mFOLFOX6 (oxaliplatin 85 mg/m\^2, folinic acid 400 mg/m\^2, fluorouracil 400 mg/m\^2 IV bolus, followed by 2400 mg/m\^2 continuous IV infusion over 46 to 48 hours on Day 1) Q2W plus IV infusion of cetuximab (loading dose of 400 mg/m\^2 on Day 1, followed by maintenance dose of 250 mg/m\^2 IV infusion every week starting on Day 8, then changed to 500 mg/m\^2 IV infusion Q2W) up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort C2A: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W + Cetuximab Q2W	Monalizumab	Participants with recurrent or metastatic 3L RAS/BRAF wild type MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W plus IV infusion of cetuximab 500 mg/m\^2 on Day 1 then 500 mg/m\^2 IV infusion Q2W starting on Day 15 up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort C2A: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W + Cetuximab Q2W	Cetuximab	Participants with recurrent or metastatic 3L RAS/BRAF wild type MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W plus IV infusion of cetuximab 500 mg/m\^2 on Day 1 then 500 mg/m\^2 IV infusion Q2W starting on Day 15 up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort C2B: Monalizumab 750 mg Q2W + Cetuximab Q2W	Cetuximab	Participants with recurrent or metastatic 3L RAS/BRAF wild type MSS-CRC will receive IV infusion of monalizumab 750 mg Q2W plus IV infusion of cetuximab 500 mg/m\^2 on Day 1 then 500 mg/m\^2 IV infusion Q2W starting on Day 15 up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-escalation Cohort 1: Monalizumab 22.5 mg Q2W + Durvalumab 1500 mg Q4W	Durvalumab	Participants will receive intravenous (IV) infusions of durvalumab 1500 mg every 4 weeks (Q4W) in combination with monalizumab 22.5 mg every 2 weeks (Q2W) up to 3 years until unacceptable toxicity, documentation of confirmed disease progression (PD), or documentation of subject withdrawal for another reason.
Dose-escalation Cohort 2: Monalizumab 75 mg Q2W + Durvalumab 1500 mg Q4W	Durvalumab	Participants will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 75 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-escalation Cohort 4: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W	Durvalumab	Participants will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-expansion Cohort: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W (Endometrial MSS)	Durvalumab	Participants with endometrial MSS will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-expansion Cohort: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W (NSCLC)	Durvalumab	Participants with non-small cell lung cancer (NSCLC) will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort A1: Monalizumab 750 mg Q2W+Durvalumab 1500 mg Q4W+mFOLFOX6 Q2W+Bevacizumab Q2W	Durvalumab	Participants with first-line (1L) MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W plus mFOLFOX (oxaliplatin 85 mg/m\^2 IV infusion, folinic acid 400 mg/m\^2 infusion, fluorouracil 400 mg/m\^2 IV bolus, followed by 2400 mg/m\^2 continuous IV infusion over 46 to 48 hours on Day 1) Q2W plus IV infusion of bevacizumab 5 mg/kg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort A1: Monalizumab 750 mg Q2W+Durvalumab 1500 mg Q4W+mFOLFOX6 Q2W+Bevacizumab Q2W	Bevacizumab	Participants with first-line (1L) MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W plus mFOLFOX (oxaliplatin 85 mg/m\^2 IV infusion, folinic acid 400 mg/m\^2 infusion, fluorouracil 400 mg/m\^2 IV bolus, followed by 2400 mg/m\^2 continuous IV infusion over 46 to 48 hours on Day 1) Q2W plus IV infusion of bevacizumab 5 mg/kg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration CohortA2: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W + mFOLFOX6 Q2W + Cetuximab Q2W	Durvalumab	Participants with 1L MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W, plus mFOLFOX6 (oxaliplatin 85 mg/m\^2, folinic acid 400 mg/m\^2, fluorouracil 400 mg/m\^2 IV bolus, followed by 2400 mg/m\^2 continuous IV infusion over 46 to 48 hours on Day 1) Q2W plus IV infusion of cetuximab (loading dose of 400 mg/m\^2 on Day 1, followed by maintenance dose of 250 mg/m\^2 IV infusion every week starting on Day 8, then changed to 500 mg/m\^2 IV infusion Q2W) up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration CohortA2: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W + mFOLFOX6 Q2W + Cetuximab Q2W	Cetuximab	Participants with 1L MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W, plus mFOLFOX6 (oxaliplatin 85 mg/m\^2, folinic acid 400 mg/m\^2, fluorouracil 400 mg/m\^2 IV bolus, followed by 2400 mg/m\^2 continuous IV infusion over 46 to 48 hours on Day 1) Q2W plus IV infusion of cetuximab (loading dose of 400 mg/m\^2 on Day 1, followed by maintenance dose of 250 mg/m\^2 IV infusion every week starting on Day 8, then changed to 500 mg/m\^2 IV infusion Q2W) up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort C1A: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W + Cetuximab Q2W	Cetuximab	Participants with recurrent or metastatic third-line (3L) RAS mutant MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W plus IV infusion of cetuximab 500 mg/m\^2 on Day 1 then 500 mg/m\^2 IV infusion Q2W starting on Day 15 up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort C1A: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W + Cetuximab Q2W	Durvalumab	Participants with recurrent or metastatic third-line (3L) RAS mutant MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W plus IV infusion of cetuximab 500 mg/m\^2 on Day 1 then 500 mg/m\^2 IV infusion Q2W starting on Day 15 up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort C1B: Monalizumab 750 mg Q2W + Cetuximab Q2W	Cetuximab	Participants with recurrent or metastatic 3L RAS mutant MSS-CRC will receive IV infusion of monalizumab 750 mg Q2W plus IV infusion of cetuximab 500 mg/m\^2 on Day 1 then 500 mg/m\^2 IV infusion Q2W starting on Day 15 up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort C2A: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W + Cetuximab Q2W	Durvalumab	Participants with recurrent or metastatic 3L RAS/BRAF wild type MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W plus IV infusion of cetuximab 500 mg/m\^2 on Day 1 then 500 mg/m\^2 IV infusion Q2W starting on Day 15 up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-escalation Cohort 2: Monalizumab 75 mg Q2W + Durvalumab 1500 mg Q4W	Monalizumab	Participants will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 75 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-escalation Cohort 3: Monalizumab 225 mg Q2W + Durvalumab 1500 mg Q4W	Monalizumab	Participants will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 225 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-escalation Cohort 4: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W	Monalizumab	Participants will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-escalation Cohort 5: Monalizumab 750 mg Q4W + Durvalumab 1500 mg Q4W	Monalizumab	Participants will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q4W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-expansion Cohort: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W (MSS-CRC)	Monalizumab	Participants with microsatellite-stable colorectal cancer (MSS-CRC) will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-expansion Cohort: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W (ovarian)	Monalizumab	Participants with ovarian cancer will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-expansion Cohort: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W (NSCLC)	Monalizumab	Participants with non-small cell lung cancer (NSCLC) will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Dose-expansion Cohort: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W (Endometrial MSS)	Monalizumab	Participants with endometrial MSS will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort A1: Monalizumab 750 mg Q2W+Durvalumab 1500 mg Q4W+mFOLFOX6 Q2W+Bevacizumab Q2W	Monalizumab	Participants with first-line (1L) MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W plus mFOLFOX (oxaliplatin 85 mg/m\^2 IV infusion, folinic acid 400 mg/m\^2 infusion, fluorouracil 400 mg/m\^2 IV bolus, followed by 2400 mg/m\^2 continuous IV infusion over 46 to 48 hours on Day 1) Q2W plus IV infusion of bevacizumab 5 mg/kg Q2W up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration CohortA2: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W + mFOLFOX6 Q2W + Cetuximab Q2W	Monalizumab	Participants with 1L MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W, plus mFOLFOX6 (oxaliplatin 85 mg/m\^2, folinic acid 400 mg/m\^2, fluorouracil 400 mg/m\^2 IV bolus, followed by 2400 mg/m\^2 continuous IV infusion over 46 to 48 hours on Day 1) Q2W plus IV infusion of cetuximab (loading dose of 400 mg/m\^2 on Day 1, followed by maintenance dose of 250 mg/m\^2 IV infusion every week starting on Day 8, then changed to 500 mg/m\^2 IV infusion Q2W) up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort C1A: Monalizumab 750 mg Q2W + Durvalumab 1500 mg Q4W + Cetuximab Q2W	Monalizumab	Participants with recurrent or metastatic third-line (3L) RAS mutant MSS-CRC will receive IV infusions of durvalumab 1500 mg Q4W in combination with monalizumab 750 mg Q2W plus IV infusion of cetuximab 500 mg/m\^2 on Day 1 then 500 mg/m\^2 IV infusion Q2W starting on Day 15 up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort C1B: Monalizumab 750 mg Q2W + Cetuximab Q2W	Monalizumab	Participants with recurrent or metastatic 3L RAS mutant MSS-CRC will receive IV infusion of monalizumab 750 mg Q2W plus IV infusion of cetuximab 500 mg/m\^2 on Day 1 then 500 mg/m\^2 IV infusion Q2W starting on Day 15 up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.
Exploration Cohort C2B: Monalizumab 750 mg Q2W + Cetuximab Q2W	Monalizumab	Participants with recurrent or metastatic 3L RAS/BRAF wild type MSS-CRC will receive IV infusion of monalizumab 750 mg Q2W plus IV infusion of cetuximab 500 mg/m\^2 on Day 1 then 500 mg/m\^2 IV infusion Q2W starting on Day 15 up to 3 years until unacceptable toxicity, documentation of confirmed PD, or documentation of subject withdrawal for another reason.

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment Emergent Serious Adverse Events (TESAEs)	Day 1 through 246.9 weeks (maximum observed duration)	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).
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Day 1 (baseline) through 246.9 weeks (maximum observed duration)	Change from baseline in SBP and DBP (minimum post baseline change \[PBC\] and maximum PBC) are reported.
Change From Baseline in Respiratory Rate (RR)	Day 1 (baseline) through 246.9 weeks (maximum observed duration)	Change from baseline in RR (minimum PBC and maximum PBC) are reported.
Change From Baseline in Body Temperature (BT)	Day 1 (baseline) through 246.9 weeks (maximum observed duration)	Change from baseline in BT (minimum PBC and maximum PBC) are reported.
Number of Participants With at Least 2-Grade Shift From Baseline in Laboratory Parameters	Day 1 (baseline) through 246.9 weeks (maximum observed duration)	Number of participants with at least 2-Grade shift from baseline in laboratory parameters are reported.
Change From Baseline in Pulse Rate (PR)	Day 1 (baseline) through 246.9 weeks (maximum observed duration)	Change from baseline in PR (minimum PBC and maximum PBC) are reported.
Change From Baseline in Oxygen Saturation (OS)	Day 1 (baseline) through 246.9 weeks (maximum observed duration)	Change from baseline in OS (minimum PBC and maximum PBC) are reported.
Number of Participants With Notable Change in QTcF and QTcB From Baseline	Day 1 (baseline) through 246.9 weeks (maximum observed duration)	Participants who had notable QTcF and QTcB interval change from baseline are reported.
Number of Participants With Dose Limiting Toxicities (DLTs)	From Day 1 to 28 days after the first dose of study drugs	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).
Percentage of Participants With Objective Response (OR) in Exploration Cohorts C1A and C1B	Baseline (Days -28 to -1) through 54.8 months (maximum observed duration)	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants With OR in Exploration Cohorts C2A and C2B	Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)	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.
Percentage of Participants With Disease Control (DC)	Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)	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).
Percentage of Participants With DC in Exploration Cohorts (C1A, C1B, C2A, and C2B)	Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)	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).
Duration of Response (DoR)	Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)	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.
Overall Survival in Exploration Cohorts (C1A, C1B, C2A, and C2B)	Baseline (-28 to -1 day) through 54.8 weeks (maximum observed duration)	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.
Percentage of Participants With OR	Baseline (Days -28 to -1) through 54.8 months (maximum observed duration)	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.
DoR in Exploration Cohorts (C1A, C1B, C2A, and C2B)	Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)	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.
Overall Survival	Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)	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.
Maximum Observed Serum Concentration (Cmax) of Monalizumab	Day 85: Pre-dose and end of infusion (within 10 minutes) after cohort specific infusions	Serum Cmax of monalizumab at pre-dose and end of infusion are reported.
Minimum Observed Serum Concentration (Cmin) of Monalizumab	Day 85: Pre-dose and end of infusion (within 10 minutes) after cohort specific infusions	Serum Cmin of monalizumab at pre-dose and end of infusion are reported.
Number of Participants With Positive ADA to Durvalumab	Day 1 through 54.8 months (Day 1 of Weeks 1, 5, 13, and 25, and 90 days after the last dose of monalizumab)	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.
Number of Participants With Positive ADA to Cetuximab	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)	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.
Progression-Free Survival (PFS)	Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)	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.
Progression-Free Survival (PFS) in Exploration Cohorts (C1A, C1B, C2A, and C2B)	Baseline (-28 to -1 day) through 54.8 months (maximum observed duration)	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.
Serum Concentration of Durvalumab	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	Serum concentration of durvalumab is reported.
Number of Participants With Positive Anti-Drug Antibodies (ADA) to Monalizumab	Day 1 through 54.8 months (Day 1 of Weeks 1, 5, 13, and 25, and 90 days after the last dose of monalizumab)	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.
Number of Participants With Human Leukocyte Antigen (HLA)-E Expression in Pretreatment Tumor Biopsies	Screening (Days -28 to -1)	The HLA-E expression in pre-treatment tumor biopsies is reported.
Serum Concentration of Cetuximab	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	Serum concentration of cetuximab is reported.
Number of Participants With Programmed Death Ligand 1 (PD-L1) Expression in Pretreatment Tumor Biopsies	Screening (Days -28 to -1)	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.