Biomarker Stratified CaboZantinib (NSC#761968) and NivOlumab (NSC#748726) (BiCaZO) - A Phase II Study of Combining Cabozantinib and Nivolumab in Participants With Advanced Solid Tumors (IO Refractory Melanoma or HNSCC) Stratified by Tumor Biomarkers - an immunoMATCH Pilot Study
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 150
- 试验地点
- 440
- 主要终点
- Objective response rate
研究概览
简要总结
This phase II trial studies the good and bad effects of the combination of drugs called cabozantinib and nivolumab in treating patients with melanoma or squamous cell head and neck cancer that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This trial may help doctors determine how quickly patients can be divided into groups based on biomarkers in their tumors. A biomarker is a biological molecule found in the blood, other body fluids, or in tissues that is a sign of a normal or abnormal process or a sign of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition. The two biomarkers that this trial is studying are "tumor mutational burden" and "tumor inflammation signature." Another purpose of this trial is to help doctors learn if cabozantinib and nivolumab shrink or stabilize the cancer, and whether patients respond differently to the combination depending on the status of the biomarkers.
详细描述
PRIMARY OBJECTIVES:
I. To evaluate the feasibility of molecular characterization based on tumor mutation burden (TMB) for participant stratification, as assessed by the proportion of participants with less than or equal to a 21-day turnaround time for biopsy results in Stage I of the study.
II. To evaluate the feasibility of molecular characterization based on TMB and Nanostring IO360 gene expression profiling assay for tumor inflammation score (TIS) for stratification, as assessed by the proportion of participants with less than or equal to a 21-day turnaround time for biopsy results in Stage II of the study.
III. To evaluate the efficacy by overall response rate (ORR - defined as confirmed and unconfirmed partial responses plus complete responses) of cabozantinib S-malate (cabozantinib) plus nivolumab in each disease cohort, stratified by TIS.
SECONDARY OBJECTIVES:
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •STEP 1 - SPECIMEN SUBMISSION
- •Participants must have histologically confirmed melanoma that is stage III or IV, unresectable, recurrent, or metastatic non-uveal melanoma OR Participants must have histologically confirmed squamous cell carcinoma of the head and neck (HNSCC) that is either locally recurrent and non-amendable to curative therapy (e.g., radiation, surgery) or metastatic. The primary tumor location must be the oropharynx, oral cavity, hypopharynx, or larynx. Primary tumor site of nasopharynx (any histology) or unknown primary tumor are not eligible
- •Note: For participants with primary oropharyngeal cancer, human papillomavirus (HPV) or p16 status must be known prior to step 1 registration
- •Participants must have disease presentation consistent with measurable disease. Note: Current disease measurements will not be required until step 2 registration
- •Participants must have had documented progression during or within 12 weeks after the last dose of PD-1 checkpoint inhibition-based therapy. Participants must have been receiving checkpoint inhibition for a minimum of 6 weeks. Participants who recur during adjuvant anti-PD1 treatment or within 12 weeks of completion of adjuvant anti-PD1 treatment are eligible if they have measurable disease and are considered unresectable
- •Participants with known human immunodeficiency virus (HIV)-infection must be receiving anti-retroviral therapy and have an undetectable viral load test within 6 months prior to step 1 registration
- •Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV viral load within 28 days prior to step 1 registration
- •Participants with a history of hepatitis C virus (HCV) infection must have no detectable viral load within 28 days prior to step 1 registration
- •Participants must not have an active infection requiring systemic therapy (except HBV, HCV or HIV as mentioned above)
- •Participants must not have experienced myocardial infarction or thromboembolic event requiring anticoagulation within 90 days prior to step 1 registration, unless clinically stable with ongoing medical management
- •Participants must have recovered to baseline or =< grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5 toxicities related to any prior treatments, unless adverse events are deemed clinically nonsignificant by the treating investigator or stable on supportive therapy
- •Participants must not have received more than one prior primary radiotherapy regimen, curative or adjuvant, to the mucosal surfaces of the head and neck, with the additional following criteria:
- •If the primary radiation is combined with chemotherapy, a minimum of 16 weeks will be required to have elapsed between the end of radiotherapy and step 1 registration. If the radiation is given alone, a minimum of 8 weeks will be required to have elapsed between the end of radiotherapy and step 1 registration
- •Additional palliative radiotherapy regimens are permitted but cannot have been administered to previously treated tissue (i.e., overlapping fields are excluded) with the exception of central nervous system (CNS) radiation and must be completed at least 4 weeks prior to step 1 registration
- •Treatment areas should be healed with no sequelae from radiation therapy (RT) that would predispose to fistula formation
- •Participants must not have received prior treatment with anti-VEGF therapies for any reason
- •Participants must be >= 18 years of age
- •Participants must have a Zubrod Performance Status 0 or 1
- •Participants must have adequate cardiac function. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification and must be class 2B or better to be eligible for this trial
- •Participants must not have any known significant organ disfunction that, in the opinion of the treating investigator, may impact suitability for receiving combination nivolumab/cabozantinib treatment
- •Participants must be able to take oral medication without breaking, opening, crushing, dissolving or chewing capsules
- •Participants must not have malabsorption syndrome
- •Participants must not have active autoimmune disease requiring systemic steroids (equivalent of > 10mg of prednisone) or other immune suppression. Exceptions:
- •Type 1 diabetes mellitus
- •Endocrinopathy only requiring hormone replacement
- •Skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic treatment
- •Conditions not expected to recur in the absence of an external trigger
- •Participants must not have received an organ allograft
- •Participants must not have a history of hemoptysis (defined as >= 1/2 tsp of bright red blood per day) or tumor bleeding within 90 days prior to step 1 registration
- •Participants must not have any of the following criteria due to the possibility of increased risk for tumor bleeding with cabozantinib 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
- •Participants must not require concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel)
- •Participants must not require anticoagulants except for the following:
- •Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
- •Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors, rivaroxaban, edoxaban, or apixaban in participants without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week prior to step 1 registration without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
- •Participants must not have evidence of preexisting uncontrolled hypertension 28 days prior to step 1 registration as documented by baseline blood pressure reading with systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 90 mmHg. Participants on antihypertensive therapies with controlled blood pressure are eligible
- •Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen
- •Participants must not be pregnant or nursing due to the known safety profiles of the drugs in this study. Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential". In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion and vasectomy with testing showing no sperm in the semen
- •Have an adequate archival tissue specimen verified by the local pathologist and documented on the Pathology Review Form from a procedure obtained after the development of resistance to anti-PD-1/L1 therapy. Archival tissue must consist of tumor block or at least 1 hematoxylin and eosin (H&E)-stained 4-5 micron slide and 20 freshly cut serially sectioned and numbered 4-5 micron unstained, uncharged slides OR
- •Be willing to undergo research biopsy AND have tumor accessible for biopsy based on the following criteria:
- •Mediastinal, laparoscopic, gastrointestinal, or bronchial endoscopic biopsies can be obtained incidentally to a clinically necessary procedure and NOT for the sole purpose of the clinical trial
- •Acceptable biopsy procedures are:
- •Percutaneous biopsy with local anesthetic and/or sedation with an expected risk of severe complications < 2%
- •Direct transoral biopsy (with or without local anesthetic and/or sedation) with an expected risk of severe complications < 2%
- •Excisional cutaneous biopsy with local anesthetic and/or sedation with an expected risk of severe complications < 2%
- •Biopsy with removal of additional tumor tissue during a medically necessary mediastinoscopy, laparoscopy, gastrointestinal endoscopy, bronchoscopy or craniotomy. No open surgical, laparoscopic or endoscopic procedure should be performed solely to obtain a biopsy for this protocol
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排除标准
- 未提供
研究组 & 干预措施
Treatment (nivolumab and cabozantinib)
Patients receive nivolumab IV over 30 minutes on day 1 of each cycle and cabozantinib PO daily. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans and collection of blood samples throughout the trial. Patients undergo a tumor biopsy during screening and optionally during follow-up.
干预措施: Biospecimen Collection (Procedure)
Treatment (nivolumab and cabozantinib)
Patients receive nivolumab IV over 30 minutes on day 1 of each cycle and cabozantinib PO daily. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans and collection of blood samples throughout the trial. Patients undergo a tumor biopsy during screening and optionally during follow-up.
干预措施: Computed Tomography (Procedure)
Treatment (nivolumab and cabozantinib)
Patients receive nivolumab IV over 30 minutes on day 1 of each cycle and cabozantinib PO daily. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans and collection of blood samples throughout the trial. Patients undergo a tumor biopsy during screening and optionally during follow-up.
干预措施: Cabozantinib S-malate (Drug)
Treatment (nivolumab and cabozantinib)
Patients receive nivolumab IV over 30 minutes on day 1 of each cycle and cabozantinib PO daily. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans and collection of blood samples throughout the trial. Patients undergo a tumor biopsy during screening and optionally during follow-up.
干预措施: Nivolumab (Biological)
Treatment (nivolumab and cabozantinib)
Patients receive nivolumab IV over 30 minutes on day 1 of each cycle and cabozantinib PO daily. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans and collection of blood samples throughout the trial. Patients undergo a tumor biopsy during screening and optionally during follow-up.
干预措施: Magnetic Resonance Imaging (Procedure)
Treatment (nivolumab and cabozantinib)
Patients receive nivolumab IV over 30 minutes on day 1 of each cycle and cabozantinib PO daily. Cycles repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients also undergo CT or MRI scans and collection of blood samples throughout the trial. Patients undergo a tumor biopsy during screening and optionally during follow-up.
干预措施: Biopsy Procedure (Procedure)
结局指标
主要结局
Objective response rate
时间窗: At the end of stage I
Confirmed and unconfirmed complete and partial responses in tumor inflammation score subgroups. Will assess biomarker response association. To test this association, will consider combination of biomarkers coded as 0 = Lo/Lo, 1 = Lo/Hi or Hi/Lo, and 2 = Hi/Hi. Assume each biomarker level is associated with an odds-ratio of approximately 3.1 (for example, corresponding to a difference in response rate of 5 percent to 14 percent from Lo/Lo to Lo/Hi or Hi/Lo). For the melanoma cohort, with approximately equal sized biomarker combination subgroups, a one-sided 0.10 level test for trend using (0,1,2) coding with logistic regression has a power of 80%. The same analysis for HNSCC will have lower power for the same effect size due to the unequal frequencies in the subgroups defined by the biomarkers. We will also conduct disease-by-biomarker interaction tests; however, there will be limited power to detect even to detect relatively large interaction parameters.
Biomarker results turnaround time
时间窗: Up to 21 days
A biomarker turnaround time estimate of at least 75% less than or equal to 21 days will be considered successful with respect to feasibility. For melanoma participants prior to Revision #7, turnaround time is defined as the time-period between date of tissue submission by the site to central repository and date the site was sent notification of participant molecular group determination. For head and neck squamous cell carcinoma (HNSCC) and melanoma participants after Revision #7, turnaround time is defined as the time-period between date of tissue submission by the site to central repository and one day after results have been received from the initial tissue submission by the Southwest Oncology Group Statistics and Data Management Center to simulate when the site would have received notification of participant molecular group determination.
Biomarker results turnaround time
时间窗: Within 21 days
A biomarker turnaround time estimate of at least 75% within 21 days will be considered successful with respect to feasibility. For melanoma participants, turnaround time is defined as the time-period between date of tissue submission by the site to central repository and date the site was sent notification of participant molecular group determination. For head and neck squamous cell carcinoma (HNSCC) participants, turnaround time is defined as the time-period between date of tissue submission by the site to central repository and one day after both results have been received by the Southwest Oncology Group Statistics and Data Management Center to simulate when the site would have received notification of participant molecular group determination.
次要结局
- Disease control rate(Up to 2 years)
- Progression-free survival(From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause, assessed up to 2 years)
- Turnaround time for the Tumor Inflammation Score in stage II(Assessed within 21 days)
- Rate and profile of >= grade 3 treatment-related adverse events(Up to 2 years)
- Overall survival(From date of registration to date of death due to any cause, assessed up to 2 years)