A Study Evaluating the Efficacy and Safety of Multiple Treatment Combinations in Patients With Melanoma (Morpheus-Melanoma)

Hoffmann-La Roche110 enrolled

Overview

This study will evaluate the efficacy, safety, and pharmacokinetics of treatment combinations in cancer immunotherapy (CIT)-naive participants with resectable Stage III melanoma (Cohort 1) and in participants with Stage IV melanoma (Cohort 2). The study is designed with the flexibility to open new treatment arms as new treatments become available, close existing treatment arms that demonstrate minimal clinical activity or unacceptable toxicity, and modify the participant population.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

110

Conditions

Melanoma

Interventions

NivolumabDRUG

Nivolumab will be administered at a dose of 3 mg/kg IV on Day 1 of each 21 day cycle.

IpilimumabDRUG

Ipilimumab will be administered at a dose of 1 mg/kg by IV on Day 1 of each 21 day cycle.

RO7247669 2100 mgDRUG

RO7247669 will be administered at a dose of 2100 mg by IV infusion on Day 1 of each 21 day cycle.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria for Cohort 1: * ECOG performance status (PS) of 0 or 1 * Histologically confirmed resectable Stage III melanoma according to AJCC-8 and no history of in-transit metastases within the last 6 months * Fit and planned for CLND * Measurable disease according to RECIST v1.1 * Availability of a representative tumor specimen * Adequate hematologic and end-organ function * For patients receiving therapeutic anticoagulation: stable anticoagulant regimen * Negative HIV test, negative hepatitis B surface antibody (HBsAb), and negative total hepatitis B core antibody (HBcAb) test, and negative hepatitis C virus (HCV) at screening. Patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count \>= 200/μL, and have an undetectable viral load. Exclusion Criteria for Cohort 1: * Mucosal, uveal and acral lentiginous melanoma * Distantly metastasized melanoma * History of in-transit metastases within the last 6 months * Prior radiotherapy * Prior immunotherapy, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, and other systemic therapy for melanoma * Treatment with investigational therapy within 28 days prior to initiation of study treatment * Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment * Prior allogeneic stem cell or solid organ transplantation * Known immunodeficiency or conditions requiring treatment with systemic immunosuppressive medication, or anticipation of need for systemic immunosuppressant medication during study treatment * Active or history of autoimmune disease or immune deficiency Inclusion Criteria for Cohort 2: * ECOG PS of 0 or 1 * Life expectancy \>= 3 months, as determined by the investigator * Histologically confirmed Stage IV (metastatic) cutaneous melanoma according to AJCC-8 * Disease progression during or following at least one but no more than two lines of treatment for metastatic disease * Measurable disease according to RECIST v1.1 * Availability of a representative tumor specimen * Adequate hematologic and end-organ function * For patients receiving therapeutic anticoagulation: stable anticoagulant regimen * Negative HIV test, negative hepatitis B surface antibody (HBsAb), and negative total hepatitis B core antibody (HBcAb) test, and negative hepatitis C virus (HCV) at screening. Patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count \>= 200/μL, and have an undetectable viral load. Exclusion Criteria for Cohort 2: * Mucosal and uveal melanoma * Treatment with investigational therapy within 28 days prior to initiation of study treatment * Treatment with systemic immunostimulatory agents within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment * Prior allogeneic stem cell or solid organ transplantation * Known immunodeficiency or conditions requiring treatment with systemic immunosuppressive medication, or anticipation of need for systemic immunosuppressant medication during study treatment * Active or history of autoimmune disease or immune deficiency * Symptomatic, untreated, or progressing CNS metastases * Active or history of carcinomatous meningitis/leptomeningeal disease * Uncontrolled tumor-related pain * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures * Uncontrolled or symptomatic hypercalcemia

Locations (14)

City of Hope

Duarte, California, United States

The Angeles Clinic and Research Institute - W LA Office

Los Angeles, California, United States

Moffitt Cancer Center

Tampa, Florida, United States

Outcomes

Primary Outcomes

Pathologic Response Rate (pRR) for Cohort 1 as Determined by Independent Pathologic Review

pRR was defined as the percentage of participants with pathologic complete response (pCR), pathologic near complete response (pnCR), and pathologic partial response (pPR) as determined by an independent pathologic review. pCR was defined as a complete absence of viable tumor cells, pnCR as \> 0 to ≤ 10% of viable tumor cells, and pPR was defined as \> 10 to ≤ 50% of viable tumor cells in the dissected lymph node. Participants with missing or no pathologic response assessment, including participants who did not proceed to complete lymph node dissection (CLND), were classified as non-responders. pRR was calculated for each arm along with 95% confidence intervals (CIs) using Clopper-Pearson method. The difference in pRR between the experimental arms and the control arm was calculated, along with 95% CIs using the Wald method with continuity correction.

Time frame: Time of surgery (scheduled at Week 7)

Objective Response Rate (ORR) for Cohort 2 as Determined by the Investigator

ORR was defined as the percentage of participants with a complete response (CR) or partial response (PR) on two consecutive occasions ≥4 weeks apart, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1). CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in the short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Participants with missing or no response assessments were classified as non-responders. ORR was calculated for each arm, along with 95% CIs using Clopper-Pearson method.

Time frame: From randomization up to approximately 3.6 months

Secondary Outcomes

pRR for Cohort 1 as Determined by Local Pathologic Assessment

pRR was defined as the percentage of participants with pCR, pnCR, and pPR as determined by a local pathologic review. pCR was defined as a complete absence of viable tumor cells, pnCR as \> 0 to ≤ 10% of viable tumor cells, and pPR was defined as \> 10 to ≤ 50% of viable tumor cells in the dissected lymph node. Participants with missing or no pathologic response assessment, including participants who did not proceed to CLND, were classified as non-responders. pRR was calculated for each arm along with 95% CIs using Clopper-Pearson method. The difference in pRR between the experimental arms and the control arm was calculated, along with 95% CIs using the Wald method with continuity correction.

Data from ClinicalTrials.gov

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Atezolizumab will be administered at a dose of 1200 mg IV on Day 1 of each 21 day cycle.

TiragolumabDRUG

Tiragolumab will be administered at a dose of 600 mg IV on Day 1 of each 21 day cycle.

RO7247669 600 mgDRUG

RO7247669 will be administered at a dose of 600 mg by IV infusion on Day 1 of each 21 day cycle.

MD Anderson Cancer Center

Houston, Texas, United States

Melanoma Institute Australia

North Sydney, New South Wales, Australia

Hopital de la Timone

Marseille, France

APHP - Hospital Saint Louis

Paris, France

Institut Universitaire du Cancer de Toulouse-Oncopole

Toulouse, France

Institut Gustave Roussy

Villejuif, France

Azienda Ospedaliera Universitaria Senese

Siena, Abruzzo, Italy

...and 4 more locations

Time frame: Time of surgery ( scheduled at Week 7)

Event-free Survival (EFS) for Cohort 1

EFS was defined as the time from randomization to any of the following events (whichever occurs first): documented disease progression (PD) that precludes surgery, as assessed by investigator per RECIST v1.1, local, regional, or distant disease recurrence, or death from any cause. PD = as at least a 20% increase in smallest sum of diameter (SOD) of target lesions, taking as reference the smallest SOD on study (including baseline). Local recurrence was defined as tumor regrowth within 2 cm of the primary lesion's tumor bed; regional recurrence as any nodal or non-nodal tumor lesions that are \> 2 cm from the primary lesion but not beyond the regional nodal basin; distant recurrence as any non-local/non-regional recurrence. Participants without disease recurrence, progression, or death at the time of analysis were censored at the time of the last tumor assessment. Kaplan-Meier method was used to estimate the median for EFS, and 95% CIs was constructed using Brookmeyer and Crowley method.

Time frame: From randomization to disease progression, disease recurrence or death or last tumor assessment (up to 22.51 months)

Relapse-free Survival (RFS) for Cohort 1

RFS was defined as the time from surgery to the first documented recurrence of disease or death from any cause. Recurrent disease includes local, regional, or distant recurrence: local recurrence was defined as tumor regrowth within 2 cm of the primary lesion's tumor bed; regional recurrence as any nodal or non-nodal tumor lesions that are more than 2 cm from the primary lesion but are not beyond the regional nodal basin; distant recurrence as any non-local/non-regional recurrence. Participants without disease recurrence or death at the time of analysis were censored at the last tumor assessment. Kaplan-Meier method was used to estimate the median for RFS, and 95% CIs were constructed using the Brookmeyer and Crowley method.

Time frame: From surgery (scheduled at Week 7) to first documented disease recurrence or death or last tumor assessment (up to 20.9 months)

Overall Survival (OS) for Cohort 1

OS was 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. Kaplan-Meier method was used to estimate the median for OS, 95% CIs were constructed using the Brookmeyer and Crowley method.

Time frame: From randomization to death from any cause or last known to be alive (Up to 25 months)

ORR for Cohort 1

ORR was defined as the percentage of participants with a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 mm. PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Participants with missing or no response assessments were classified as non-responders. ORR was calculated for each arm, along with 95% CIs using the Clopper-Pearson method. The difference in ORR between the experimental arms and the control arm was calculated, along with 95% CIs using the Wald method with continuity correction.

Time frame: Prior to surgery (up to Week 6)

Number of Participants With Adverse Events (AEs) and Severity of AEs Determined According to National Cancer Institute Common Terminology Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0) for Cohort 1

An AE is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. Severity was determined per NCI CTCAE v5.0 Grade 1: Mild; asymptomatic or mild symptoms; clinical/diagnostic observations only; or intervention not indicated; Grade 2:Moderate; minimal, local/non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living (ADL); Grade 3: Severe or medically significant, but not immediately life-threatening: hospitalization or prolongation of hospitalization indicated; disabling or limiting self-care ADL; Grade 4: Life-threatening consequences or urgent intervention indicated; Grade 5: Death related to AE. Multiple occurrences of AEs in the same category at the worst (highest) NCIC-CTCAE grade for an individual are counted only once.

Time frame: From initiation of study treatment up to 135 days (Serious AEs and AESI) or 30 days (all other AEs) after the final dose of study treatment or until initiation of new systemic anti-cancer therapy (Up to 5.6 months)

Number of Participants With Immune-related AEs Grade ≥ 3 for Cohort 1

An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with the use of an investigational product, whether or not considered related to the investigational product. Participants with immune-related adverse events Grade ≥ 3 were reported.

Time frame: From initiation of study treatment up to 135 days after the final dose of study treatment (Up to 5.6 months)

Rate of Delayed Surgery Due to Treatment-related AEs

Rate of delayed surgery due to treatment related AEs was defined as the percentage of participants for whom surgery was delayed due to treatment-related AEs for more than 2 weeks. An AE was any untoward medical occurrence in a clinical investigation participants administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with the use of the investigational product, whether considered related to the investigational product.

Time frame: Time of surgery (scheduled at Week 7) up to 40.1 weeks

Duration of Surgery Delay Due to Treatment-related AEs

Duration of surgery delay due to treatment related AEs was calculated on the participants for whom surgery was delayed due to treatment-related AEs for more than 2 weeks. An AE was any untoward medical occurrence in a clinical investigation participants administered a pharmaceutical product, regardless of causal attribution. An AE can therefore be any unfavorable \& unintended sign (including an abnormal laboratory finding), symptom/disease temporally associated with the use of the investigational product, whether considered related to the investigational product.

Time frame: Time of surgery (scheduled at Week 7) up to 40.1 weeks

Surgical Complication Rates for Cohort 1

Surgical complications were scored according to the Clavien-Dindo surgical classification. Complication rates for every grade were reported and scored for participants who underwent CLND. The Surgical complications according to Clavien-Dindo can be classified into the following grades: Grade I: Any complication that does not need pharmacological treatment or surgical, endoscopic, and radiological interventions. Grade II: Complications that require pharmacological treatment with drugs or blood transfusions and total parenteral nutrition. Grade III: Complications that require surgical, endoscopic, or radiological intervention with (Grade IIIb) or without (Grade IIIa) general anesthesia. Grade IV: Life-threatening complications requiring intensive care unit (ICU) management, which may be single organ (Grade IVa) or multiorgan (Grade IVb) dysfunction. Grade V: Complications that might cause the death of a participant. Values have been rounded off to 2 decimal digits.

Time frame: At treatment discontinuation visit (Week 13) and Surgery Follow-Up (6 months after surgery)

Progression-Free Survival (PFS) for Cohort 2

PFS after randomization/enrollment was defined as the time from randomization/enrollment to the first occurrence of disease progression or death from any cause (whichever occurred first), as determined by the investigator according to RECIST v1.1. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on the study (including baseline) and/or unequivocal progression of a non-target lesion and/or any new lesion. Participants without documented disease progression or death at the time of analysis were censored at the day of the last tumor assessment. Kaplan-Meier method was used to estimate the median for PFS, with 95% CIs constructed by using the Brookmeyer and Crowley method.

Time frame: From randomization/enrollment to first documented disease progression or death or last tumor assessment (up to 3.6 months)

OS for Cohort 2

OS was 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. Kaplan-Meier method was used to estimate the median for OS, with 95% CIs constructed by using the Brookmeyer and Crowley method.

Time frame: From randomization/enrollment to death from any cause or last known to be alive (Up to 24.2 months)

OS Rates at Specific Timepoints for Cohort 2

OS was defined as the time from randomization to death from any cause. OS rate is percentage of participants who were event free for OS. Participants who were still alive at the time of OS analysis were censored at the last date they were known to be alive. OS rate at specific time points were estimated using the Kaplan-Meier method, with 95% CIs calculated based on Greenwood's estimate for the variance.

Time frame: Months 3, 6 and 12

Duration of Response (DOR) for Cohort 2

DOR was defined as the time from the first occurrence of a documented objective response (OR) to disease progression or death from any cause (whichever occurred first), as determined by the investigator according to RECIST v1.1. OR was defined as a CR or PR on two consecutive occasions ≥ 4 weeks apart, as determined by the investigator according to RECIST v1.1. CR = disappearance of all target lesions or any pathological lymph nodes (whether target or non-target) having a reduction in short axis to \<10 mm. PR = at least a 30% decrease in the SOD of all target lesions, taking as reference the baseline SOD, in the absence of CR. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on the study (including baseline). Participants without PD or death at time of analysis were censored at time of last tumor assessment. Kaplan-Meier method was used to estimate median for DOR, with 95% CIs constructed using Brookmeyer \& Crowley method.

Time frame: Time from the first occurrence of a documented OR to disease progression or death from any cause (up to 3.6 months)

Disease Control Rate (DCR) for Cohort 2

DCR was defined as the percentage of participants with stable disease for ≥ 12 weeks or a CR or PR, as determined by the investigator according to RECIST v1.1. CR was defined as the disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of diameters of all target lesions, taking as reference the baseline sum of diameters, in the absence of CR. Stable disease was defined as neither sufficient shrinkage to qualify for CR or PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the SOD of target lesions, taking as reference the smallest SOD on the study (including baseline). DCR was calculated for each treatment arm, with 95% CIs estimated through use of Clopper-Pearson's exact method.

Time frame: From randomization up to 3.6 months

Number of Participants With AEs and Severity of AEs Determined According to NCI CTCAE v5.0 for Cohort 2

An AE=any untoward medical occurrence in clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. AE can therefore be any unfavorable \& unintended sign, symptom/disease temporally associated with using an investigational product, whether or not considered related to the investigational product. Severity was determined per NCI CTCAE v5.0 Grade 1: Mild; asymptomatic/mild symptoms; clinical/diagnostic observations only; or intervention not indicated; Grade 2: Moderate; minimal, local/non-invasive intervention indicated; or limiting age-appropriate instrumental activities of daily living (ADL); Grade 3: Severe/medically significant, but not immediately life-threatening: hospitalization/prolongation of hospitalization indicated; disabling/limiting self-care ADL; Grade 4: Life-threatening consequences/urgent intervention indicated; Grade 5: Death related to AE. Multiple occurrences of AEs in 1 individual are counted once at highest grade.