A Phase II/III Trial of Chemotherapy + Cetuximab vs Chemotherapy + Bevacizumab vs Atezolizumab + Bevacizumab Following Progression on Immune Checkpoint Inhibition in Recurrent/Metastatic Head and Neck Cancers

  • STATUS
    Recruiting
  • End date
    Dec 15, 2027
  • participants needed
    430
  • sponsor
    National Cancer Institute (NCI)
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Updated on 23 October 2022
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Summary

This phase II/III compares the standard therapy (chemotherapy plus cetuximab) versus adding bevacizumab to standard chemotherapy, versus combination of just bevacizumab and atezolizumab in treating patients with head and neck cancer that has spread to other places in the body (metastatic or advanced stage) or has come back after prior treatment (recurrent). Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Bevacizumab is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Cetuximab is in a class of medications called monoclonal antibodies. It binds to a protein called EGFR, which is found on some types of cancer cells. This may help keep cancer cells from growing. Cisplatin and carboplatin are in a class of chemotherapy medications known as platinum-containing compounds. They work by killing, stopping, or slowing the growth of cancer cells. Docetaxel is in a class of chemotherapy medications called taxanes. It stops cancer cells from growing and dividing and may kill them. The addition of bevacizumab to standard chemotherapy or combination therapy with bevacizumab and atezolizumab may be better than standard chemotherapy plus cetuximab in treating patients with recurrent/metastatic head and neck cancers.

Description

PRIMARY OBJECTIVES:

I. To evaluate progression-free survival (PFS) of patients treated with chemotherapy plus cetuximab, chemotherapy plus bevacizumab, and atezolizumab plus bevacizumab. (Phase II) II. To evaluate the overall survival (OS) of patients treated with chemotherapy plus cetuximab to the superior arm from the phase II portion of the protocol. (Phase III)

SECONDARY OBJECTIVES:

I. To evaluate the OS for the subset of patients with high PD-L1 expression, defined as combined positive score (CPS) >= 20% on all arms of treatment.

II. To evaluate the toxicity of each arm of treatment.

IMAGING OBJECTIVES:

I. To establish the correlation between fludeoxyglucose F-18 (18F-FDG) positron emission tomography (PET) and computed tomography (CT) neck imaging biomarkers (maximum standard uptake value [SUVmax], metabolic tumor volume [MTV], total lesion glycolysis [TLG], tumor volume) and expression of PD-L1 expression (Low versus high, defined as CPS < 20 versus CPS >= 20).

II. To determine if 18FDG-PET/CT and CT neck imaging biomarkers at baseline will predict treatment response at nine to twelve weeks post the initiation of treatment, PFS, and OS.

EXPLORATORY OBJECTIVE:

I. To establish the correlation between 18F-FDG PET and CT neck radiomics features and PD-L1 expressions (Low versus high - defined as CPS < 20 versus CPS >= 20).

OUTLINE: This is a randomized phase II trial followed by a randomized phase III trial.

PHASE II: Patients are randomized to 1 of 3 arms.

ARM A: Patients receive cetuximab intravenously (IV) over 60-120 minutes on days 1, 8, and 15 of each cycle, docetaxel IV over 1 hour on day 1 of each cycle, and cisplatin IV or carboplatin IV on day 1 of each cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive cetuximab IV over 60-120 minutes on day 1 of each cycle of maintenance therapy. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, a PET scan, and/or magnetic resonance imaging (MRI) throughout the trial.

ARM B: Patients receive bevacizumab IV over 30-90 minutes on day 1 of each cycle, docetaxel IV over 1 hour on day 1 of each cycle, and cisplatin IV or carboplatin IV on day 1 of each cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive bevacizumab IV over 30-60 minutes on day 1 of each cycle of maintenance therapy. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, a PET scan, and/or MRI throughout the trial.

ARM C: Patients receive bevacizumab IV over 30-90 minutes on day 1 and atezolizumab over 30-60 minutes on day 1 of each cycle. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, a PET scan, and/or MRI throughout the trial.

PHASE III: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive cetuximab IV over 60-120 minutes on days 1, 8, and 15 of each cycle, docetaxel IV over 1 hour on day 1 of each cycle, and cisplatin IV or carboplatin IV on day 1 of each cycle. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients then receive cetuximab IV over 60-120 minutes on day 1 of each cycle of maintenance therapy. Cycles repeat every 21 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo a CT scan, a PET scan, and/or MRI throughout the trial.

ARM B: Patients receive treatment as in Arm B or C above based on results of the Phase II trial.

After completion of study treatment, patients are followed up at 30 days and then every 3 months if patient is < 2 years from randomization and every 6 months if patient is 2-5 years from randomization.

Details
Condition Clinical Stage IV HPV-Mediated (p16-Positive) Oropharyngeal Carcinoma AJCC v8, Metastatic Head and Neck Squamous Cell Carcinoma, Metastatic Hypopharyngeal Squamous Cell Carcinoma, Metastatic Laryngeal Squamous Cell Carcinoma, Metastatic Lip and Oral Cavity Carcinoma, Metastatic Nasal Cavity Squamous Cell Carcinoma, Metastatic Nasopharyngeal Squamous Cell Carcinoma, Metastatic Pharyngeal Squamous Cell Carcinoma, Metastatic Sinonasal Squamous Cell Carcinoma, Recurrent Head and Neck Squamous Cell Carcinoma, Recurrent Hypopharyngeal Squamous Cell Carcinoma, Recurrent Laryngeal Squamous Cell Carcinoma, Recurrent Lip and Oral Cavity Squamous Cell Carcinoma, Recurrent Nasopharyngeal Squamous Cell Carcinoma, Recurrent Pharyngeal Squamous Cell Carcinoma, Recurrent Sinonasal Squamous Cell Carcinoma, Stage IV Hypopharyngeal Carcinoma AJCC v8, Stage IV Laryngeal Cancer AJCC v8, Stage IV Lip and Oral Cavity Cancer AJCC v8, Stage IV Nasopharyngeal Carcinoma AJCC v8, Stage IV Oropharyngeal (p16-Negative) Carcinoma AJCC v8, Stage IV Sinonasal Cancer AJCC v8
Treatment Cetuximab, cisplatin, computed tomography, magnetic resonance imaging, positron emission tomography, docetaxel, carboplatin, bevacizumab, Atezolizumab
Clinical Study IdentifierNCT05063552
SponsorNational Cancer Institute (NCI)
Last Modified on23 October 2022

Eligibility

 Yes No Not Sure

Inclusion Criteria

Patient must have histologically confirmed squamous cell carcinoma of the head and neck (HNSCC) (excluding SCC of salivary glands, and skin)
Patient must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Measurements must be obtained within 4 weeks prior to randomization
Patient must be >= 18 years of age
Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Patient must have received prior therapy with an immune checkpoint inhibitor (ICI) in the first-line setting for recurrent/metastatic disease with at least stable disease for at least 12 weeks by RECIST. Prior combination immunotherapies are permitted, but patient must not have had any prior chemotherapy, cetuximab or any prior antiangiogenic treatment (e.g., bevacizumab, ziv-aflibercept, ramucirumab, sorafenib, sunitinib, pazopanib, regorafenib, lenvatinib, etc.). Patient must have completed any prior investigational therapy at least 28 days prior to randomization
NOTE: Patients who received chemotherapy or cetuximab in combination with radiation for curative-intent treatment of locally-advanced disease and did not progress for at least 6 months thereafter, will not be excluded
Patient must have PD-L1 expression >= 1% by CPS in the tumor and/or immune cells
NOTE: Enrolling centers should test for PD-L1 CPS preferably using the SP263 assay. Where this is not feasible, any using their preferred Clinical Laboratory Improvement Act (CLIA)-certified assay will be accepted. It is preferred for standard of care (SOC) PD-L1 assessments to be done on post-first line ICI samples if available, but SOC PD-L1 assessments on pre-ICI samples will be accepted for eligibility
Patient must have the ability to understand and the willingness to sign a written
informed consent document. Patients with impaired decision-making capacity
(IDMC) who have a legally authorized representative (LAR) or caregiver and/or
family member available will also be considered eligible
Leukocytes >= 3,000/mcL (must be obtained =< 14 days prior to protocol randomization)
Absolute neutrophil count (ANC) >= 1,500/mcL (must be obtained =< 14 days prior to protocol randomization)
Platelets >= 100,000/mcL (must be obtained =< 14 days prior to protocol randomization)
Hemoglobin (Hgb) > 9 g/dL (must be obtained =< 14 days prior to protocol randomization) (Note: Patient may be transfused to meet this criteria)
Total bilirubin =< 2.0 x institutional upper limit of normal (ULN) (=< 5.0 x institutional ULN if hepatic metastases present or =< 3 x ULN for patients with known Gilbert's disease) (must be obtained =< 14 days prior to protocol randomization)
Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional ULN (< 5.0 x institutional ULN if hepatic metastases present) (must be obtained =< 14 days prior to protocol randomization)
Alkaline phosphatase < 2.5 x institutional ULN (< 5.0 x institutional ULN if hepatic or bone metastases present) (must be obtained =< 14 days prior to protocol randomization)
Creatinine =< 1.5 x institutional ULN (must be obtained =< 14 days prior to protocol randomization)
Patients with uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN) must have their calcium levels corrected prior to randomization
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. Patients must not have untreated brain metastases or leptomeningeal disease
Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial

Exclusion Criteria

Patient must not have a history of >= grade 3 immune-related adverse event on prior ICI therapy. Patients who developed grade 3 endocrinopathies but are now stable on hormone supplementation and/or a daily prednisone dose of =< 10 mg (or equivalent doses of another glucocorticoid), will be permitted on this trial
Patient must not have a history of PD-1 inhibitor-induced hyper-progression, defined as 100% increase in tumor burden within 8 weeks (or 50% within 4 weeks) of initiating ICI and associated with clinical deterioration
Patient must not have any of the following criteria due to the possibility of increased risk for tumor bleeding with bevacizumab therapy
Prior carotid bleeding
Tumors that invade major vessels (e.g., the carotid) as shown unequivocally by imaging studies
Central (e.g., within 2 cm from the hilum) lung metastases that are cavitary as shown unequivocally by imaging studies
Any prior history of bleeding related to the current head and neck cancer
History of gross hemoptysis (bright red blood of 1/2 teaspoon or more per episode of coughing) within 3 months prior to randomization
Patient must not have uncontrolled hypertension, a history of hypertensive crisis or
hypertensive encephalopathy, or a history of grade 4 thromboembolism
Patient must not have a history of coagulopathy or hemorrhagic disorders
Patient must not have a history of thrombosis (e.g., pulmonary embolism or deep venous thrombosis) currently requiring therapeutic anticoagulation (prophylactic use of anticoagulation is allowed)
Patient must not be receiving chronic daily treatment with aspirin (> 325 mg/day) or non-steroidal anti-inflammatory agents (NSAID's) known to inhibit platelet function. The use of anti-platelet agents [e.g., dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix)] is allowed only if patient is not receiving aspirin or NSAID's known to inhibit platelet function. The use of direct oral anticoagulant therapies such as dabigatran (Pradaxa) and rivaroxaban (Xarelto) is not allowed while on study due to bleeding risk
Patient must not have a severe infection within 4 weeks prior to randomization, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. Patients must not have active tuberculosis
Patient must not have a history of non-infectious pneumonitis requiring steroids at doses greater than or equal to 10 mg per day of prednisone or the equivalent on first line immunotherapy
Patient must not have a history of solid organ transplantation or stem-cell transplant
Patient must not be on immunosuppressive medication within 7 days prior to randomization except for: intranasal, inhaled, or topical steroids, local steroid injection, systemic corticosteroids at doses less than or equal to 10 mg per day of prednisone or the equivalent, or steroids used as premedication for hypersensitivity reactions
Patient must not have an active autoimmune disease that requires systemic treatment within 2 years prior to randomization. Patients who are receiving replacement therapy for adrenal or pituitary insufficiency will not be excluded
Patient must not have had a severe hypersensitivity reaction to any of the drug components used on this protocol or to chimeric or humanized antibodies or fusion proteins
Patient must not have received any live vaccine within 30 days prior to randomization and while participating in the study (and continue for 5 months after the last dose of atezolizumab on Arm C). Live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, rabies, bacillus Calmette-Guerin (BCG), and typhoid (oral) vaccine. Patients are permitted to receive inactivated vaccines and any non-live vaccines including those for the seasonal influenza and COVID-19 (Note: intranasal influenza vaccines, such as Flu-Mist are live attenuated vaccines and are not allowed). If possible, it is recommended to separate study drug administration from vaccine administration by about a week (primarily, in order to minimize an overlap of adverse events
Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used
All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy
A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)
Patients must not expect to conceive or father children by using accepted and
effective method(s) of contraception or by abstaining from sexual intercourse
for the duration of their participation in the study and for 2 months after
the last dose of treatment for patients assigned to Arm A and for 6 months
after the last dose of protocol treatment for patients assigned to Arms B or
C
NOTE: Patients must also not breastfeed while on treatment and for 2 months after the last dose of treatment for patients assigned to Arm A and for 6 months after the last dose of treatment for patients assigned to Arms B or C
Patients must not have uncontrolled pleural effusion, pericardial effusion, or ascites
requiring recurrent drainage procedures (once monthly or more frequently)
Patients may have indwelling catheters (e.g., PleurX)
Patient must not have significant cardiovascular disease (such as New York Heart Association class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to randomization, or unstable arrhythmia or unstable angina at the time of randomization
Patient must not receive any other chemotherapy, immunotherapy, antitumor hormonal therapy (excluding contraceptives and replacement steroids), radiation therapy, or experimental medications while on protocol treatment. Symptomatic lesions (e.g., bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to randomization and patients must be recovered from the effects of radiation (there is no required minimum recovery period
Patient must not have had a surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to randomization, or anticipation of need for major surgical procedure while on protocol treatment
Patient must not have any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of the agents used in this protocol, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
Patient must not have a history of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess, or active GI bleeding within 6 months prior to randomization
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