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)
- Conditions
- Squamous Cell Carcinoma of the Head and Neck
- Interventions
- Registration Number
- NCT05459129
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 12
- 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 antigen (HBsAg) test at screening
- Positive hepatitis B surface antibody (HBsAb) test at screening, or negative HBsAb at screening accompanied by either of the following: Negative total hepatitis B core antibody (HBcAb), Positive total hepatitis B core antibody (HBcAb) followed by a negative quantitative hepatitis B virus (HBV) DNA.
- 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)
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Atezo + Tira Tiragolumab 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. Atezo + Tira Atezolizumab 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. Atezo + Tira + CP Atezolizumab 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. Atezo + Tira + CP Tiragolumab 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. Atezo + Tira + CP Carboplatin 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. Atezo + Tira + CP Paclitaxel 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.
- Primary Outcome Measures
Name Time Method Percentage of Participants With Pathologic Complete Response (pCR) as Determined by Local Pathologic Review At the time of surgery (Week 7 ± 1 week) pCR was defined as the absence of any viable primary tumor at time of surgical resection, as determined by local pathologic review. The pCR rate was defined as the percentage of participants who achieved a pCR. pCR rate was calculated for each arm, along with the 95% confidence interval (CI) estimated using the Clopper-Pearson method and the 95% CI for difference in rates was estimated using the Wald method with continuity correction. Participants with missing or no pathologic response assessment were classified as non-responders. Percentages have been rounded off to the nearest whole number.
- Secondary Outcome Measures
Name Time Method Pathologic Response Rate (pRR) as Determined by Local Pathologic Review At the time of surgery (Week 7 ± 1 week) pRR was defined as the percentage of participants with a pCR, major pathological response (mPR), and pathological partial response (pPR). pCR was defined as the absence of any viable primary tumor at time of surgical resection, as determined by local pathologic review. mPR was defined as ≤10% residual viable tumor at the time of surgical resection in the primary tumor. pPR was defined as ≤ 50% residual viable tumor at the time of surgical resection in the primary tumor. pRR was calculated for each arm, along with the 95% CI, estimated using the Clopper-Pearson method, and the 95% CI for the difference in rates was estimated using the Wald method with continuity correction. Percentages have been rounded off to the nearest whole number.
Event-Free Survival (EFS) From randomization to PD disease recurrence or death (Up to 9.2 months) EFS was defined as the time from randomization to disease progression (PD) that precludes surgery, as determined by the investigator according to Response Evaluation Criteria in Solid Tumors, Version 1.1 (RECIST v1.1); local, regional, or distant disease recurrence or death from any cause, whichever occurs first. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline), and must also demonstrate an absolute increase of ≥ 5 millimeters (mm). Kaplan-Meier method was used to estimate the median for EFS, and 95% Cls was constructed using Brookmeyer and Crowley method. Data from participants who have not experienced such events were censored at the time of the last tumor assessment. Due to the early termination of the study, the limited sample size and follow-up time no meaningful conclusions can be made in terms of median EFS per arm or HR between the arms.
Relapse-Free Survival (RFS) From surgery (scheduled at Week 7 ± 1 week) to first documented disease recurrence or death (up to 7.6 months) RFS was defined as the time from surgery to the first documented recurrence of disease or death from any cause. Recurrent disease included local, regional, or distant recurrence: local recurrence was defined as tumor regrowth within 2 centimeter (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 who did not have documented recurrence of disease or died, RFS was censored at the day of the last tumor assessment. Kaplan-Meier method was used to estimate the median for RFS, and 95% Cls was constructed using Brookmeyer and Crowley method. Due to the early termination of the study, the limited sample size and follow-up time no meaningful conclusions can be made in terms of median RFS per arm or HR between the arms.
Overall Survival (OS) From randomization to death from any cause or last known to be alive (Up to 9.2 months) OS was defined as the time from randomization to death from any cause. Data from 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, and 95% Cls was constructed using Brookmeyer and Crowley method. Due to the early termination of the study, the limited sample size and follow-up time no meaningful conclusions can be made in terms of median OS and no further OS analysis are reported.
Objective Response Rate (ORR) Prior to surgery (up to Week 6) ORR was defined as the percentage of participants with an objective tumor response of complete response (CR) or partial response (PR) as determined by the investigator using RECIST v.1.1. CR was defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) have a reduction in short axis to \<10 millimeters (mm). PR was defined as at least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD. ORR was calculated for each arm, along with 95% CIs, using the Clopper-Pearson method and the 95% CI for difference in rates was estimated using the Wald method with continuity correction. Participants with missing or no response assessments were classified as non-responders.
Landmark EFS Rate 3 Months, 6 Months, and 1 Year EFS was defined as the time from randomization to PD that precludes surgery, as determined by the investigator according to RECIST v1.1; local, regional, or distant disease recurrence or death from any cause, whichever occurs first. EFS rate was defined as the percentage of participants who are event-free at the specified timepoints. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum of diameters at prior timepoints (including baseline), and must also demonstrate an absolute increase of ≥ 5 mm. Landmark EFS rates were estimated for each study arm using the Kaplan-Meier method, with 95% CIs calculated through the use of Greenwood's formula. Percentages have been rounded off to the nearest whole number. Due to the early termination of the study, the limited sample size and follow-up time no meaningful conclusions can be made.
Landmark RFS Rate 3 Months, 6 Months, and 1 Year RFS was defined as the time from surgery to the first documented recurrence of disease or death from any cause. RFS rate was defined as the percentage of participants who are event-free at the specified timepoints. Recurrent disease included 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. Landmark RFS rates were estimated for each study arm using the Kaplan-Meier method, with 95% CIs calculated through the use of Greenwood's formula. Percentages have been rounded off to the nearest whole number. Due to the early termination of the study, the limited sample size and follow-up time no meaningful conclusions can be made .
Landmark OS Rate 3 Months, 6 Months, and 1 Year OS was defined as the time from randomization to death from any cause. OS rate was defined as the percentage of participants who are event-free at the specified timepoints. Landmark OS rates were estimated for each study arm using the Kaplan-Meier method, with 95% CIs calculated through the use of Greenwood's formula. Due to the early termination of the study, the limited sample size and follow-up time no meaningful conclusions can be made .
Number of Participants With Adverse Events (AEs) From initiation of study treatment up to 135 days after the final dose of study treatment (up to 5.1 months) An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptoms, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product.
Number of Participants With Immune-Related AEs Grade >=3 Up to 12 weeks An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptoms, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Grade 3 AEs were defined as severe or medically significant, but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care activities of daily living.
Rate of Delayed Surgery Due to Treatment-Related AEs Delay up to week after the planned time of surgery (scheduled at Week 7 ± 1 week) up to 2 weeks (up to Week 9) 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 2 weeks. An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptoms, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product.
Duration of Delayed Surgery Due to Treatment-Related AEs Delay up to week after the planned time of surgery (scheduled at Week 7 ± 1 week) up to 2 weeks (up to Week 9) 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 2 weeks. An AE was any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including abnormal laboratory values or abnormal clinical test results), symptoms, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product.
Rate of Surgical Complications as Assessed According to the Clavien-Dindo Surgical Classification From Surgery (Week 7 ± 1 week) up to 5.1 months Surgical complications were scored according to Clavien-Dindo surgical classification. Complication rates for every grade were reported \& scored for participants who underwent complete lymph node dissection (CLND). The Surgical complications according to Clavien-Dindo can be classified into 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. Only categories with non-zero data was reported.
Trial Locations
- Locations (6)
Hadassah University Hospital - Ein Kerem
🇮🇱Jerusaelm, Israel
City of Hope
🇺🇸Duarte, California, United States
Thomas Jefferson University Hospital
🇺🇸Philadelphia, Pennsylvania, United States
University of Pittsburgh Medical Center
🇺🇸Pittsburgh, Pennsylvania, United States
Severance Hospital - Yonsei Cancer Center
🇰🇷Seoul, South Korea
Asan Medical Center
🇰🇷Seoul, South Korea
Hadassah University Hospital - Ein Kerem🇮🇱Jerusaelm, Israel