A Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic Colorectal Cancer (Morpheus-CRC)

Study Overview
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Brief Summary
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A phase Ib/II, open-label, multicenter, randomized study designed to assess the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of immunotherapy-based treatment combinations in patients with metastatic colorectal cancer (mCRC) that became refractory to first- and second-line standard therapies. Eligible patients will be assigned to one of several treatment arms.

Official Title
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A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating the Efficacy and Safety of Multiple Immunotherapy-Based Treatment Combinations in Patients With Metastatic Colorectal Cancer (Morpheus-CRC)

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Regorafenib
* Drug: Atezolizumab
* Drug: Imprime PGG
* Drug: Bevacizumab
* Drug: Isatuximab
* Drug: Selicrelumab
* Drug: Idasanutlin
* Drug: AB928
* Genetic: LOAd703


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 Life expectancy ≥ 3 months, as determined by the investigator Histologically confirmed adenocarcinoma originating from the colon or rectum Metastatic disease not amenable to local treatment Disease progression during or following not more than two separate lines of treatment for metastatic colorectal cancer (mCRC) that consisted of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy in combination with a biologic agent Measurable disease (at least one target lesion) according to RECIST v1.1 Adequate hematologic and end-organ function obtained within 14 days prior to initiation of study treatment Exclusion Criteria: High microsatellite instability (MSI-H) tumor Presence of BRAFV600E mutation Prior treatment with any of the protocol-specified study treatments Prior treatment with T-cell co-stimulating or immune checkpoint blockade therapies including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies Biologic treatment within 2 weeks prior to initiation of study treatment, or other systemic treatment for CRC within 2 weeks or 5 half-lives of the drug (whichever is shorter) prior to initiation of study treatment Treatment with investigational therapy within 28 days prior to initiation of study treatment Eligibility only for the control arm Prior allogeneic stem cell or solid organ transplantation Treatment with systemic immunostimulatory agents within 4 weeks or 5 half-lives of the drug (whichever is longer) prior to the initiation of study treatment Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressant medication during study treatment Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab Current treatment with anti-viral therapy for HBV Uncontrolled pleural effusion, pericardial effusion, ascites requiring recurrent drainage procedures (once monthly or more frequently), or tumor related-pain, Uncontrolled or symptomatic hypercalcemia (ionized calcium >1.5 mmol/L, calcium >12 mg/dL, or corrected serum calcium >ULN) Symptomatic, untreated, or actively progressing CNS metastases History of leptomeningeal disease Active or history of autoimmune disease or immune deficiency History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan History of malignancy other than CRC within 2 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death Active tuberculosis Severe infection within 4 weeks prior to initiation of study treatment Significant cardiovascular disease Grade ≥3 hemorrhage or bleeding event within 28 days prior to initiation of study treatment Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins Inability to swallow medications Malabsorption condition that would alter the absorption of orally administered medications Evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding Urine dipstick ≥ 2+ protein or ≥ 3.5 g of protein in a 24-hour urine collection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Regorafenib (Control)<br>Participants will receive treatment until unacceptable toxicity or disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1. | Drug: Regorafenib<br>* Regorafenib will be administered orally on Days 1-21 of each 28-day cycle.<br>|
| Experimental: Atezolizumab + Imprime PGG + Bevacizumab<br>Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of 21-day cycles, with the exception of the Atezolizumab + Selicrelumab + Bevacizumab, Atezolizumab + Idasanutlin, Atezolizumab + Regorafenib and Atezolizumab + Regorafenib + AB928 arms where the Atezolizumab will be administered by IV infusion every 2 weeks (Q2W) on Days 1 and 15 of each 28-day cycle.<br>Drug: Imprime PGG<br>* Imprime PGG will be administered by IV infusion weekly on Days 1, 8, and 15 of each 21-day cycle.<br>Drug: Bevacizumab<br>* Bevacizumab will be administered by IV infusion on Day 1 of each 21-day cycle for the Atezolizumab + Imprime PGG + Bevacizumab arm, and on Day 1 and Day 15 of each 28-day cycle for the Atezolizumab + Selicrelumab + Bevacizumab arm.<br>|
| Experimental: Atezolizumab + Isatuximab<br>Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of 21-day cycles, with the exception of the Atezolizumab + Selicrelumab + Bevacizumab, Atezolizumab + Idasanutlin, Atezolizumab + Regorafenib and Atezolizumab + Regorafenib + AB928 arms where the Atezolizumab will be administered by IV infusion every 2 weeks (Q2W) on Days 1 and 15 of each 28-day cycle.<br>Drug: Isatuximab<br>* Isatuximab will be administered on Day 1, 8 and 15 of cycle 1 and on day 1 of all subsequent cycles. Cycles will be 21 days long.<br>|
| Experimental: Atezolizumab + Selicrelumab + Bevacizumab<br>Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of 21-day cycles, with the exception of the Atezolizumab + Selicrelumab + Bevacizumab, Atezolizumab + Idasanutlin, Atezolizumab + Regorafenib and Atezolizumab + Regorafenib + AB928 arms where the Atezolizumab will be administered by IV infusion every 2 weeks (Q2W) on Days 1 and 15 of each 28-day cycle.<br>Drug: Bevacizumab<br>* Bevacizumab will be administered by IV infusion on Day 1 of each 21-day cycle for the Atezolizumab + Imprime PGG + Bevacizumab arm, and on Day 1 and Day 15 of each 28-day cycle for the Atezolizumab + Selicrelumab + Bevacizumab arm.<br>Drug: Selicrelumab<br>* Selicrelumab will be administered by subcutaneous (SC) injection on Day 1 of cycles 1-4 and every third cycle thereafter. Cycles will be 28 days long.<br>|
| Experimental: Atezolizumab + Idasanutlin<br>Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of 21-day cycles, with the exception of the Atezolizumab + Selicrelumab + Bevacizumab, Atezolizumab + Idasanutlin, Atezolizumab + Regorafenib and Atezolizumab + Regorafenib + AB928 arms where the Atezolizumab will be administered by IV infusion every 2 weeks (Q2W) on Days 1 and 15 of each 28-day cycle.<br>Drug: Idasanutlin<br>* Idasanutlin will be administered orally on Days 1-5 of each 28-day cycle.<br>|
| Experimental: Atezolizumab + Regorafenib<br>Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | Drug: Regorafenib<br>* Regorafenib will be administered orally on Days 1-21 of each 28-day cycle.<br>Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of 21-day cycles, with the exception of the Atezolizumab + Selicrelumab + Bevacizumab, Atezolizumab + Idasanutlin, Atezolizumab + Regorafenib and Atezolizumab + Regorafenib + AB928 arms where the Atezolizumab will be administered by IV infusion every 2 weeks (Q2W) on Days 1 and 15 of each 28-day cycle.<br>|
| Experimental: Atezolizumab + Regorafenib + AB928<br>Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | Drug: Regorafenib<br>* Regorafenib will be administered orally on Days 1-21 of each 28-day cycle.<br>Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of 21-day cycles, with the exception of the Atezolizumab + Selicrelumab + Bevacizumab, Atezolizumab + Idasanutlin, Atezolizumab + Regorafenib and Atezolizumab + Regorafenib + AB928 arms where the Atezolizumab will be administered by IV infusion every 2 weeks (Q2W) on Days 1 and 15 of each 28-day cycle.<br>Drug: AB928<br>* AB928 will be administered orally once daily on Days 1-28 of each 28-day cycle.<br>|
| Experimental: Atezolizumab + LOAd703<br>Participants will receive treatment until unacceptable toxicity or loss of clinical benefit as confirmed by disease progression per RECIST V1.1 or lack of continued benefit as determined by the investigator. | Drug: Atezolizumab<br>* Atezolizumab will be administered by intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of 21-day cycles, with the exception of the Atezolizumab + Selicrelumab + Bevacizumab, Atezolizumab + Idasanutlin, Atezolizumab + Regorafenib and Atezolizumab + Regorafenib + AB928 arms where the Atezolizumab will be administered by IV infusion every 2 weeks (Q2W) on Days 1 and 15 of each 28-day cycle.<br>Genetic: LOAd703<br>* LOAd703 will be administered by intratumoral injection on Day 1 of each 21-day cycle.<br>* Other names: Delolimogene mupadenorepvec;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best Confirmed Overall Response Rate (ORR) as Determined by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 | The best confirmed overall response rate (ORR) is defined as the percentage of participants with a complete response or partial response on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to RECIST v1.1. Participants could be classified as Stable Disease if the assessment was at least 6 weeks from randomization. Participants were classified as Missing if no post-baseline response assessments were available. Participants were classified as Not Evaluable if all post-baseline response assessments were unevaluable. The differences in ORR between the experimental arms and the corresponding control arm were calculated, along with 95% confidence intervals (CIs), using normal approximation of the binomial distribution. The 95% CIs for ORRs were constructed using the Clopper-Pearson method. The 95% CIs for the difference in rates were constructed using the Wald method with continuity correction. | From randomization until disease progression or loss of clinical benefit (up to 4 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) as Determined by Investigator According to RECIST v1.1 | Progression-free survival (PFS) after randomization, defined as the time from randomization to the first occurrence of disease progression or death from any cause (whichever occurs first), was determined by the investigator according to RECIST v1.1. For participants who did not have documented disease progression or death, PFS was censored at the day of the last tumor assessment. The Kaplan-Meier method was used to estimate the median for PFS with 95% confidence intervals (CIs) constructed through use of the Brookmeyer and Crowley method. | From randomization up to the first occurrence of disease or death from any cause (up to 4 years) | 
| Overall Survival (OS) | Overall survival (OS) is defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. The Kaplan-Meier method was used to estimate the median for OS with 95% confidence intervals (CIs) constructed through use of the Brookmeyer and Crowley method. | From randomization up to death from any cause (up to 4 years) | 
| Percentage of Participants Who Were Alive at Landmark Timepoints for Overall Survival (OS) | Overall survival (OS) is defined as the time from randomization to death from any cause. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. OS is shown as the percentage of participants who were event-free at the landmark timepoints of 3, 6, 12, and 18 months. | 3, 6, 12, and 18 months | 
| Duration of Response (DOR) as Determined by the Investigator According to RECIST v1.1 | Duration of response is defined as the time from the first occurrence of a documented objective response to disease progression or death from any cause. | From the date of first occurrence of a documented objective response to disease progression or death from any cause, whichever occurs first (up to 4 years) | 
| Disease Control Rate (DCR), as Determined by the Investigator Per RECIST v1.1 | Disease control rate is defined as the percentage of participants with stable disease for ≥12 weeks or a complete or partial response, as determined by the investigator according to RECIST v1.1. | From randomization until disease progression or loss of clinical benefit (up to 4 years) | 
| Percentage of Participants With at Least One Adverse Event (AE) | The incidence, nature, and severity of adverse events (AEs) are reported, with severity determined according to NCI CTCAE v4.0. All AEs were reported until 30 days after the last study dose or until start of new systemic anti-cancer therapy. Serious AEs and AEs of special interest were reported until 135 days (or 180 days for the Atezolizumab + LOAd703 arm only) after the last dose of study treatment. | Adverse event data were collected from baseline up to 6 months after the last dose of study treatment (up to 640 days); deaths (all-cause) were reported from baseline through survival follow-up (up to 4 years) |