A Multicenter Phase II Trial of Paclitaxel With and Without Nivolumab in Taxane Naive, and Nivolumab and Cabozantinib in Taxane Pretreated Subjects With Angiosarcoma
A Multicenter Phase II Trial of Paclitaxel With and Without Nivolumab in Taxane Naive, and Nivolumab and Cabozantinib in Taxane Pretreated Subjects With Angiosarcoma
This phase II trial studies how well paclitaxel with and without nivolumab works in treating patients with soft tissue sarcoma that have not received taxane drugs, and how well nivolumab and cabozantinib work in treating taxane pretreated patients with soft tissue sarcoma. Nivolumab works through the body's immune system to help the immune system act against tumor cells. Chemotherapy drugs, such as paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. This trial is being done to see if the combination of nivolumab and paclitaxel or cabozantinib can shrink soft tissue sarcoma and possibly prevent it from coming back.
PRIMARY OBJECTIVES:
I. To determine the progression free survival (PFS) for paclitaxel with and without nivolumab in subjects with taxane naive angiosarcoma.
II. To determine the overall response rate (ORR) of nivolumab in combination with cabozantinib S-malate (cabozantinib) in patients with taxane pre-treated angiosarcoma.
SECONDARY OBJECTIVES:
I. To determine the ORR of paclitaxel in combination with nivolumab. II. To determine clinical activity of the addition of nivolumab to paclitaxel or cabozantinib in subjects with angiosarcoma by determination of overall survival (OS) for each combination.
III. To determine clinical activity of the addition of nivolumab to cabozantinib in subjects with taxane pre-treated angiosarcoma by determination of progression free survival (PFS) at 6 months by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 criteria.
IV. To assess toxicity of the concurrent nivolumab-paclitaxel and nivolumab-cabozantinib combinations in subjects with angiosarcoma based on National Cancer Institute (NCI)-Common Terminology Criteria for Adverse Events (CTCAE) v.5.0.
V. To measure symptomatic adverse events (AE) for patients via Patient Reported Outcome (PRO)-CTCAE, Functional Assessment of Cancer Therapy General (FACT-G) questionnaire, and Linear Analogue Self-Assessment (LASA).
OUTLINE: Patients who have not previously received a taxane are randomized to Arm I or Arm II. Patients who have previously received a taxane are assigned to Arm III.
ARM I: Patients receive nivolumab intravenously (IV) over 30 minutes on day 1 and paclitaxel IV over 1 hour on days 1, 8, and 15. Cycles repeat every 4 weeks for up to 2 years (24 months) for patients who achieve complete response (CR), partial response (PR) or stable disease (SD) on immunotherapy/nivolumab, or in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Cycles repeat every 4 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity. Patients with disease progression may crossover to Arm III.
ARM III (EFFECTIVE OF 10/28/2021, NEW PATIENT ACCRUAL PERMANENTLY CLOSED): Patients receive nivolumab IV over 30 minutes on day 1 and cabozantinib orally (PO) daily. Cycles repeat every 4 weeks for up to 2 years (24 months) for patients who achieve CR, PR or SD on immunotherapy/nivolumab, or in the absence of disease progression or unacceptable toxicity.
Patients also undergo collection of blood at baseline and on study, computed tomography (CT) scan, spiral CT, or magnetic resonance imaging (MRI), or FDG-positron emission tomography (FDG-PET) scan throughout the trial.
After completion of study treatment, patients are followed up every 3 months for 3 years.
Inclusion Criteria:
Histologically confirmed cutaneous or visceral angiosarcoma, where curative treatment is either not possible or curative modality therapy is declined by the subject. Note: If a subject declines curative modality therapy, the reason must be documented (e.g. excessive morbidity to necessary surgery)
Note: Radiation induced angiosarcomas are permitted
Must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Per RECIST v1.1, clinical lesions will only be considered measurable when they are superficial and >= 10 mm diameter as assessed using calipers or ruler (e.g. skin nodules). For the case of skin lesions, documentation by color photography including a ruler to estimate the size of the lesion is required. When lesions can be evaluated by both clinical exam and imagining, imaging evaluation should be undertaken since it is more objective and may also be reviewed at the end of the study. The same method of measurement should be used throughout the study, preferably performed by the same investigator. Areas previously radiated must have demonstrated disease progression at some point over the past 6 months and growth must be subsequent to the last line of anti-cancer directed therapy (e.g. chemotherapy, radiation therapy, surgery)
Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown
Age >= 18 years
Eastern Cooperative Oncology Group (ECOG) performance status 0-1
Prior Treatment
Patient must have completed all prior cancer directed therapies (including investigational) >= 7 days prior to cycle 1 day 1
There is no limit to overall number of prior lines of therapy
No prior PD-1 inhibitor or PD-L1 inhibitor therapy is permitted
No prior administration of VEGF TKI therapy is permitted
Recovery to baseline or' =< grade 1 CTCAE version 5.0 from toxicity related to any prior treatment, unless adverse events are clinically non-significant and/or stable on supportive therapy, with the exception of fatigue (which should be =< grade 2) or alopecia. Note: Patients should be expected to have experienced any nadir and have adequate blood count recovery prior to cycle 1 day 1
Taxane Naive Patients Only: No prior exposure to taxane therapy of any duration for angiosarcoma
Taxane Pre-treated Patients Only (Effective 10/28/2021, new patient accrual to Arm 3 was permanently closed): Prior taxane therapy is allowed at any point prior to registration as long as prior treatment eligibility criteria are met prior to cycle 1 day 1
No major surgery (except the diagnostic biopsy) =< 28 days of study registration. Procedures such as thoracentesis, paracentesis, percutaneous biopsy, Lasik eye surgery are not considered major surgery. Subjects with clinically relevant ongoing complications from prior surgery are not eligible
Absolute neutrophil count (ANC) >= 1,500/mm^3
Platelet count >= 100,000/mm^3
Hemoglobin >= 9.0 g/dL
Calculated (Calc.) creatinine clearance >= 30 mL/min (per Cockcroft-Gault)
Total bilirubin =< 1.5 x upper limit of normal (ULN)
Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
Urine protein:creatinine (UPC) ratio < 1 or urine protein =< 1+ (Only for Arm 3 Taxane pre-treated and crossover patients)
No uncontrolled central nervous system (CNS) metastases. Patients with history of CNS metastasis will be allowed as long as the metastatic sites were adequately treated as demonstrated by clinical and radiographic improvement, and the patient has recovered from the intervention (no residual adverse events > CTCAE grade 1), and the patient has remained without recurrence of new or worsening CNS symptoms for a period of 28 days prior to registration. Treated CNS metastasis (mets) should have no ongoing requirement for steroids, and no evidence of hemorrhage after treatment for at least 28 days prior to registration
No uncontrolled intercurrent illness that would put the patient at undue risk by participation in the study, in the opinion of the investigator
No history of syncope of cardiovascular etiology, uncontrolled cardiac arrhythmia, history of Mobitz II second degree or third degree heart block without a permanent pacemaker in place, myocardial ischemia or infarction, severe or unstable angina, New York Heart Association (NYHA) class II to IV heart failure, or stroke/transient ischemic attack (TIA) within the past 3 months
No thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 1 month before randomization. Subjects with a diagnosis of incidental, subsegmental pulmonary embolism (PE) or deep vein thrombosis (DVT) within 6 months are allowed if stable, asymptomatic, and treated with low molecular weight heparin (LMWH) for at least 2 weeks before first dose. Iatrogenic arterial embolization procedures such as tumor arterial embolization or splenic artery embolization are allowed
Patients with a requirement for steroid treatment or other immunosuppressive treatment: Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
Patients are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger (precipitating event)
Active autoimmune disease requiring systemic treatment (i.e. disease modifying agents, corticosteroids, or immunosuppressive drugs) within the past 2 years. These include but are not limited to patients with a history of immune-related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as systemic lupus erythematosus (SLE), rheumatoid arthritis, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
No planned palliative procedures for alleviation of pain such as radiation therapy or surgery
No untreated or impending spinal cord compression or evidence of spinal metastases with a risk of impending fracture or spinal cord compression
No known or suspected contraindications or hypersensitivity to paclitaxel, cabozantinib or nivolumab or to any of the excipients
Disorders associated with a high risk of perforation or fistula formation: active inflammatory bowel disease, active diverticulitis, active cholecystitis, active symptomatic cholangitis or active appendicitis, active acute pancreatitis or active acute obstruction of the pancreatic or biliary duct, or active gastric outlet obstruction; abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before randomization. Note: Complete healing of an intra-abdominal abscess must be confirmed before randomization
No clinically significant hematuria, hematemesis, or hemoptysis, or other history of significant bleeding (e.g., pulmonary hemorrhage) within 3 months before randomization
No lesions invading major pulmonary blood vessels
No other clinically significant disorders: uncompensated/symptomatic hypothyroidism; requirements for hemodialysis or peritoneal dialysis; history of solid organ transplantation
Serious non-healing wounds unrelated to cancer are excluded
Chronic concomitant treatment with strong inhibitors and inducers of CYP3A4 is not allowed on this study. Patients on strong CYP3A4 inhibitors and inducers must discontinue the drug 7 days and 14 days, respectively prior to registration on the study
Taxane Naive Patients Only: No clinically significant neuropathy (grade >= 2 per NCI CTCAE v5.0)
Taxane Pre-treated only (Effective 10/28/2021, new patient accrual to Arm 3 was permanently closed):
No clinical, laboratory or radiographic evidence of an active bacterial, fungal, or viral infection requiring treatment at the time of registration. No concurrent use of parenteral (IV) antibiotics is permitted. Oral antibiotics administered for a defined course with expectation of resolution of infection are permitted at the discretion of the investigator
No use of ongoing systemic steroid therapy within 7 days prior to study registration. Dose equivalence of prednisone 10mg daily or less is permitted
Taxane Pre-treated only:
Patients must be able to speak and comprehend English or Spanish in order to complete the mandatory patient-completed measures
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Age >= 18 years
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): ECOG performance status 0-1
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Prior Treatment
Patient must have completed all prior treatments (including investigational Arm 2 paclitaxel) >= 28 days prior to cycle 1 day 1
No prior PD-1 inhibitor or PD-L1 inhibitor therapy is permitted
Recovery to baseline, or =< grade 1 CTCAE version 5.0 from toxicity related to any prior treatment, unless adverse events are clinically non-significant and/or stable on supportive therapy, with the exception of fatigue (which should be =< grade 2) or alopecia. Note: Patients should be expected to have experienced any nadir and have adequate blood count recovery prior to cycle 1 day 1
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): No major surgery (except the diagnostic biopsy) =< 28 days of study re-registration. Procedures such as thoracentesis, paracentesis, percutaneous biopsy, Lasik eye surgery are not considered major surgery. Subjects with clinically relevant ongoing complications from prior surgery are not eligible
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Absolute neutrophil count (ANC) >= 1,500/mm^3
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Platelet count >= 100,000/mm^3
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Hemoglobin >= 9.0 g/dL
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Calc. creatinine clearance >= 30 mL/min (per Cockcroft-Gault)
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Total bilirubin =< 1.5 x upper limit of normal (ULN)
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): AST/ALT =< 2.5 x upper limit of normal (ULN)
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): UPC ratio < 1 or urine protein =< 1+
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): No uncontrolled CNS metastases. Patients with history of CNS metastasis will be allowed as long as the metastatic sites were adequately treated as demonstrated by clinical and radiographic improvement, and the patient has recovered from the intervention (no residual adverse events > CTCAE grade 1), and the patient has remained without recurrence of new or worsening CNS symptoms for a period of 28 days prior to registration. Treated CNS mets should have no ongoing requirement for steroids, and no evidence of hemorrhage after treatment for at least 28 days prior to registration
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): No uncontrolled intercurrent illness that would put the patient at undue risk by participation in the study, in the opinion of the investigator
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): No history of syncope of cardiovascular etiology, uncontrolled cardiac arrhythmia, History of Mobitz II second degree or third degree heart block without a permanent pacemaker in place, myocardial ischemia or infarction, severe or unstable angina, New York Heart Association (NYHA) class II to IV heart failure, or stroke/transient ischemic attack (TIA) within the past 3 months
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): No thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 1 month before randomization. Subjects with a diagnosis of incidental, subsegmental PE or DVT within 6 months are allowed if stable, asymptomatic, and treated with LMWH for at least 2 weeks before first dose. Iatrogenic arterial embolization procedures such as tumor arterial embolization or splenic artery embolization are allowed
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Patients with a requirement for steroid treatment or other immunosuppressive treatment: Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. Patients are permitted to use topical, ocular, intra-articular, intranasal, and inhalational corticosteroids (with minimal systemic absorption). A brief course of corticosteroids for prophylaxis (e.g., contrast dye allergy) or for treatment of non-autoimmune conditions (e.g., delayed-type hypersensitivity reaction caused by contact allergen) is permitted
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): Active autoimmune disease requiring systemic treatment (i.e. disease modifying agents, corticosteroids, or immunosuppressive drugs) within the past 2 years. These include but are not limited to patients with a history of immune-related neurologic disease, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barre syndrome, myasthenia gravis; systemic autoimmune disease such as SLE, rheumatoid arthritis, connective tissue diseases, scleroderma, inflammatory bowel disease (IBD), Crohn's, ulcerative colitis, hepatitis; and patients with a history of toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, or phospholipid syndrome should be excluded because of the risk of recurrence or exacerbation of disease
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): No planned palliative procedures for alleviation of pain such as radiation therapy or surgery
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): No untreated or impending spinal cord compression or evidence of spinal metastases with a risk of impending fracture or spinal cord compression
Re-Registration Eligibility Criteria (upon progression on Arm 2 only): No known or suspected contraindications or hypersensitivity to cabozantinib or nivolumab or to any of the exc
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New York, New York 10032, United States
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