A Study Evaluating Efficacy and Safety of Multiple Treatment Combinations in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck (Morpheus-Head and Neck Cancer)

Study Overview
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Brief Summary
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This is a Phase Ib/II, open-label, multicenter, randomized, umbrella study in participants with locally advanced squamous cell carcinoma of the head and neck (SCCHN). The study will enroll treatment-naive participants with resectable Stage III-IVA human papillomavirus (HPV)-negative, programmed death-ligand 1 (PD-L1)-positive SCCHN with measurable disease, as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1) who have not received systemic treatment for their disease.

Official Title
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A Phase Ib/II, Open-Label, Multicenter, Randomized Umbrella Study Evaluating The Efficacy and Safety of Multiple Treatment Combinations in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck (Morpheus-Head and Neck Cancer)

Conditions
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Squamous Cell Carcinoma of the Head and Neck

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: Tiragolumab
* Drug: Carboplatin
* Drug: Paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group Performance Status of 0 or 1 Histologically confirmed, resectable Stage III-IVA SCCHN Eligible candidate for R0 resection with curative intent at the time of screening HPV-negative test for oropharyngeal carcinoma, as determined locally by p16 immunohistochemistry (IHC), in situ hybridization, or polymerase chain reaction-based assay Measurable disease (at least one target lesion), as assessed according to RECIST v1.1 PD-L1 expression, defined as a combined positive score (CPS) >= 1 Adequate hematologic and end-organ function Negative HIV test with the following exception: 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. Negative hepatitis B surface antibody (HBsAb) and negative total hepatitis B core antibody (HBcAb) test, negative hepatitis C virus (HCV) at screening Exclusion Criteria: HPV-positive oropharyngeal cancer, as determined locally by p16 IHC, in situ hybridization, or by polymerase chain reactions-based assay Distantly metastasized SCCHN Any prior therapy for SCCHN, including immunotherapy, chemotherapy, or RT Prior treatment with any of the protocol-specified study treatments Treatment with investigational therapy within 42 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 Treatment with systemic immunosuppressive medication within 2 weeks prior to initiation of 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 study treatment or within 5 months after the final dose of study treatment 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 SCCHN within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5 -year OS rate>90%) Active tuberculosis Severe infection within 4 weeks prior to initiation of study treatment Treatment with therapeutic or prophylactic oral or intravenous (IV) antibiotics within 2 weeks prior to initiation of study treatment Significant cardiovascular disease such a New York Heart Association cardiac disease (Class II or greater), myocardial infarction or cerebrovascular accident within 3 months prior to initiation of study treatment, unstable arrhytmia, or unstable angina Major surgical procedure, other than for diagnosis, within 4 weeks prior to study initiation of study treatment, or anticipation of need for a major surgical procedure other than tumor resection, during the study Any of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of investigational drug, may affect the interpretation of the results, impair the ability of the patient to participate in the study, or renders the patient at high risk form treatment complications History of severe allergic reactions to chimeric or humanized antibodies or fusion proteins Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies Known allergy or hypersensitivity to any of the study drugs or their excipients Known intolerance to any of the drugs required for premedication Pregnancy or breastfeeding, or intention of becoming pregnant during the study Eligible only for the control arm Active EBV infection or known or suspected chronic EBV infection at screening Specific Exclusion Criteria for Atezo+Tira+CP: Known severe allergy or hypersensitivity to placlitaxel, platinum or platinum-containing compounds Known history of severe hypersensitivity to products containing Cremophor EL Creatinine clearance <45m./min (Calculated using the Cockcroft-Gault formula)

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: Atezo + Tira<br>Participants in the atezolizumab plus tiragolumab arm will receive treatment for two cycles (6 weeks) until surgery or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. | Drug: Atezolizumab<br>* Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.<br>* Other names: Tecentriq;Drug: Tiragolumab<br>* Tiragolumab will be administered intravenously at a fixed dose of 600 mg on Day 1 of each 21-day cycle.<br>|
| Experimental: Atezo + Tira + CP<br>Participants in the atezolizumab plus tiragolumab plus carboplatin plus paclitaxel arm arm will receive treatment for two cycles (6 weeks) until surgery or until unacceptable toxicity or loss of clinical benefit, whichever occurs first. | Drug: Atezolizumab<br>* Atezolizumab will be administered intravenously at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.<br>* Other names: Tecentriq;Drug: Tiragolumab<br>* Tiragolumab will be administered intravenously at a fixed dose of 600 mg on Day 1 of each 21-day cycle.<br>Drug: Carboplatin<br>* Carboplatin will be administered intravenously at a dose of area under the concentration-time curve (AUC) 5 mg/mL/min on Day 1 of each 21 day cycle.<br>Drug: Paclitaxel<br>* Paclitaxel will be administered intravenously at a dose of 175 mg/m2 on Day 1 of each 21 day cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Complete Response (pCR), as Determined by Local Pathologic Review | pCR is defined as the absence of any viable primary tumor at time of surgical resection, as determined by local pathologic review. | At the time of surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathologic Response Rate (pRR), as Determined by Local Pathologic Review | pRR is defined as the proportion of participants with a pCR, mPR (defined as <=10% residual viable tumor at the time of surgical resection in the primary tumor) and pPR (defined as <=50% residual viable tumor at the time of surgical resection in the primary tumor). | At the time of surgery | 
| Event-Free Survival (EFS) | EFS is defined as the time from randomization to any of the following events (whichever occurs first): disease progression that precludes surgery, as determined by the investigator according to RECIST v1.1, local, regional, or distant disease recurrence, or death from any cause. | Randomization up to approximately 5 years | 
| Relapse-Free Survival (RFS) | RFS is defined as the time from surgery to the first documented recurrence of disease or death from any cause. | Surgery up to approximately 5 years | 
| Overall Survival (OS) | OS is defined as the time from randomization to death from any cause. | Randomization up to approximately 5 years | 
| Objective Response Rate (ORR) | ORR is defined as the proportion of patients with a complete response or a partial response, as determined by the investigator according to RECIST v1.1, prior to surgery. | After completion of neoadjuvant treatment | 
| Percentage of Participants With Adverse Events | Percentage of participants with adverse events. | Up to 5 years after first participant enrolled | 
| Percentage of Participants with Immune-Related Adverse Events Grade >=3 | Percentage of immune-related adverse events Grade >=3 | Up to Week 12 after first participant enrolled | 
| Rate of Delayed Surgery Due to Treatment-Related Adverse Events | Percentage of participants with >=2 weeks delay in surgery from planned surgery due to treatment-related adverse events. | >=2 weeks delay from the planned surgery | 
| Duration of Delayed Surgery Due to Treatment-Related Adverse Events | Duration of delay defined as time from planned surgery to the actual surgery date. | >=2 weeks delay from the planned surgery | 
| Surgical Complication Rates | Surgical complications will be scored according to Clavien-Dindo classification. | From surgery through follow-up (up to approximately 5 years) | 
| Landmark EFS | Landmark EFS is defined as the time from randomization to any of the following events (whichever occurs first): disease progression that precludes surgery, as determined by the investigator according to RECIST v1.1; local, regional, or distant disease recurrence; or death from any cause at specified timepoints (1, 2, 3, and 5 years) | Randomization to specified timepoints (1, 2, 3, and 5 years) | 
| Landmark RFS | Landmark RFS is defined as the time from surgery to the first documented recurrence of disease or death from any cause at specified timepoints (1, 2, 3, and 5 years) | From surgery to specified timepoints (1, 2, 3, and 5 years) | 
| Landmark OS | Landmark OS is defined as the time from randomization to death from any cause at specified timepoints (1, 2, 3, and 5 years) | Randomization to specified timepoints (1, 2, 3, and 5 years |