Clinical Trials /

Testing the Addition of Nivolumab to Chemotherapy in Treatment of Soft Tissue Sarcoma

NCT04339738

Description:

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.

Related Conditions:
  • Angiosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of Nivolumab to Chemotherapy in Treatment of Soft Tissue Sarcoma
  • Official Title: A Multicenter Phase II Trial of Paclitaxel With and Without Nivolumab in Taxane Naive, and Nivolumab and Cabozantinib in Taxane Pretreated Subjects With Angiosarcoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-02153
  • SECONDARY ID: NCI-2020-02153
  • SECONDARY ID: A091902
  • SECONDARY ID: A091902
  • SECONDARY ID: U10CA180821
  • NCT ID: NCT04339738

Conditions

  • Skin Angiosarcoma
  • Skin Radiation-Related Angiosarcoma
  • Visceral Angiosarcoma

Interventions

DrugSynonymsArms
Cabozantinib S-malateBMS-907351, Cabometyx, Cometriq, XL-184, XL184Arm III (nivolumab, cabozantinib S-malate)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm I (nivolumab, paclitaxel)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm I (nivolumab, paclitaxel)

Purpose

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.

Detailed Description

      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.

      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) version (v).5.0.

      V. To measure symptomatic adverse events (AE) for patients via Patient Reported Outcome
      (PRO)-CTCAE.

      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 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 in the absence of disease progression or unacceptable toxicity. Patients with disease
      progression may crossover to Arm III.

      ARM III: Patients receive nivolumab IV over 30 minutes on day 1 and cabozantinib orally (PO)
      daily. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable
      toxicity.

      After completion of study treatment, patients are followed up every 3 months for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (nivolumab, paclitaxel)ExperimentalPatients receive nivolumab IV over 30 minutes on day 1 and paclitaxel IV over 1 hour on days 1, 8, and 15. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
  • Nivolumab
  • Paclitaxel
Arm II (paclitaxel)ExperimentalPatients receive paclitaxel IV over 1 hour on days 1, 8, and 15. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
  • Paclitaxel
Arm III (nivolumab, cabozantinib S-malate)ExperimentalPatients receive nivolumab IV over 30 minutes on day 1 and cabozantinib S-malate PO daily. Cycles repeat every 4 weeks in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib S-malate
  • Nivolumab

Eligibility Criteria

        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

                    -  All local diagnostic slides AND 5 x 4-6 micron unstained slides from
                       diagnostic tumor tissue should be available for retrospective central
                       pathology review

          -  Must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST)
             version (v)1.1. Per RECIST v1.1, clinical lesions will only be considered measurable
             when they are superficial and P10 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

               -  Therefore, for women of childbearing potential only, a negative pregnancy test
                  done =< 3 days prior to registration is required

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Prior Treatment

               -  Patient must have completed all prior treatments (including investigational) >=
                  28 days prior to cycle 1 day 1

                    -  Exception: prostate patients who are allowed to concurrently receive
                       androgen suppression therapy

                    -  Exception: Targeted small molecule chemotherapy or radiation must be
                       completed >= 14 days of day 1 of study treatment. For targeted
                       chemotherapies, prior therapies must be completed prior to registration and
                       final dose must have occurred > 5 half-lives 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 nonsignificant and/or
                  stable on supportive therapy, with the exception of fatigue (which should be =<
                  grade 2) or alopecia

          -  Taxane Naive Patients Only: No prior exposure to taxane therapy of any duration for
             angiosarcoma

          -  Taxane Pre-treated Patients Only: Prior taxane therapy is allowed at any point prior
             to registration as long as it is >= 28 days 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) >= 1,000/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)

               -  For patients with documented/suspected Gilbert's disease, bilirubin =< 3 x ULN

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 2.5 x upper limit
             of normal (ULN)

               -  For patients with significant hepatic metastases, ALT and AST =< 5 x ULN. No
                  clinically active or chronic liver disease resulting in moderate/severe hepatic
                  impairment (Child-Pugh class B or C), ascites, coagulopathy or bleeding due to
                  liver dysfunction

          -  Urine protein:creatinine (UPC) ratio < 1 or urine protein =< 1+

          -  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

               -  Note: Patients are permitted to enroll if they have vitiligo; type I diabetes
                  mellitus; hypothyroidism, pituitary or adrenal insufficiency requiring only
                  hormone replacement; psoriasis not requiring systemic treatment, or conditions
                  not expected to recur in the absence of an external trigger (precipitating event)

          -  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: serious non-healing wound or ulcer;
             malabsorption syndrome; uncompensated/symptomatic hypothyroidism; requirements for
             hemodialysis or peritoneal dialysis; history of solid organ transplantation

          -  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:

               -  Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI),
                  or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis,
                  pulmonary embolism) within 6 months before first dose. Subjects with a diagnosis
                  of DVT within 6 months are allowed if stable and treated with LMWH for at least 2
                  weeks before first dose

               -  No history of clinically significant coagulopathy. The subject has prothrombin
                  time (PT)/international normalized ratio (INR) or partial thromboplastin time
                  (PTT) test =< 1.3 x the laboratory ULN within 7 days before the first dose of
                  study treatment

               -  No uncontrolled hypertension, defined as systolic blood pressure of > 140 mmHg or
                  diastolic pressure > 90 mmHg on anti-hypertensive medications

               -  No known or suspected gastrointestinal disorder affecting absorption of oral
                  medications (for patients getting cabozantinib)

          -  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:

               -  No current use of aspirin (> 81 mg/day), or any other antiplatelet agents

               -  Concomitant anticoagulation with oral anticoagulants (e.g., warfarin, direct
                  thrombin inhibitors, and factor Xa inhibitors) or platelet inhibitors (e.g.,
                  clopidogrel) is not permitted. Low-dose (prophylactic) low molecular weight
                  heparins (LMWH) are permitted. Anticoagulation with therapeutic doses of LMWH is
                  allowed in subjects with no known brain metastases, no clinically significant
                  hemorrhage, or no complications from a thromboembolic event on the
                  anticoagulation regimen, and who have been on a stable dose of LMWH for at least
                  2 weeks before first dose

          -  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

               -  Therefore, for women of childbearing potential only, a negative pregnancy test
                  done =< 3 days prior to re-registration is required

          -  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

                    -  Exception: prostate patients who are allowed to concurrently receive
                       androgen suppression therapy

                    -  Note: Re-registration is only permitted after progression on Arm 2

               -  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 nonsignificant and/or
                  stable on supportive therapy, with the exception of fatigue (which should be =<
                  grade 2) or alopecia

          -  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) >= 1,000/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)

               -  For patients with documented/suspected Gilbert's disease, bilirubin =< 3 x ULN

          -  Re-Registration Eligibility Criteria (upon progression on Arm 2 only): AST/ALT =< 2.5
             x upper limit of normal (ULN)

               -  For patients with significant hepatic metastases, ALT and AST =< 5 x ULN. No
                  clinically active or chronic liver disease resulting in moderate/severe hepatic
                  impairment (Child-Pugh class B or C), ascites, coagulopathy or bleeding due to
                  liver dysfunction

          -  Re-Registration Eligibility Criteria (upon progression on Arm 2 only): UPC ratio < 1
             or urine p
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS) in taxane naive patients with angiosarcoma
Time Frame:From registration (randomization) to either progression or death (without progression), assessed up to 3 years
Safety Issue:
Description:Will compare the PFS in taxane naive angiosarcoma patients receiving either (1) paclitaxel + nivolumab compared to (2) paclitaxel alone.

Secondary Outcome Measures

Measure:ORR in the nivolumab + paclitaxel
Time Frame:Up to 3 years
Safety Issue:
Description:Will be estimated by dividing the number of evaluable patients that achieve a confirmed response by the total number of evaluable patients in the nivolumab + paclitaxel combination arm. Additionally a 95% confidence interval will be constructed utilizing properties of the binomial distribution.
Measure:Overall survival in each of the 2 combination arms
Time Frame:From study enrollment until death due to any cause, assessed up to 3 years
Safety Issue:
Description:Will be evaluated using the Kaplan-Meier method in order to determine the median survival rate. This median survival rate will be calculated for each of the 2 combination arms (i.e. nivolumab + paclitaxel and nivolumab + cabozantinib).
Measure:PFS rate
Time Frame:At 6 months
Safety Issue:
Description:
Measure:Incidence of adverse events
Time Frame:Up to 3 years
Safety Issue:
Description:Maximum grade adverse events will be summarized by treatment arm in a tabular setting. This will be done both with and without regard to the assigned attribution of each adverse event.
Measure:Patient-reported outcomes (PRO)
Time Frame:Up to 3 years
Safety Issue:
Description:Will be assessed via PRO-Common Terminology Criteria for Adverse Events (CTCAE). In order to evaluate this endpoint we will calculate the proportion of patients that report a grade 3+ event along with a 95% confidence interval based on the properties of the binomial distribution. Any other analyses with these data will be done in an exploratory and hypothesis generating manner.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 22, 2021