Clinical Trials /

Cabozantinib Combined With PD-1 and CTLA-4 Inhibition in Metastatic Soft Tissue Sarcoma

NCT04551430

Description:

The hypothesis of this study is that the response rate of soft tissue sarcoma will be improved with the addition of PD-1 and CTLA-4 inhibition to cabozantinib, and that cabozantinib priming will increase the response to nivolumab and ipilimumab.

Related Conditions:
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib Combined With PD-1 and CTLA-4 Inhibition in Metastatic Soft Tissue Sarcoma
  • Official Title: A Randomized Phase II Trial of Cabozantinib Combined With PD-1 and CTLA-4 Inhibition in Metastatic Soft Tissue Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: 20-x270
  • NCT ID: NCT04551430

Conditions

  • Metastatic Soft-tissue Sarcoma

Interventions

DrugSynonymsArms
CabozantinibCohort A: Cabozantinib
NivolumabOpdivoCohort B: Cabozantinib + Nivolumab + Ipilimumab
IpilimumabYervoyCohort B: Cabozantinib + Nivolumab + Ipilimumab

Purpose

The hypothesis of this study is that the response rate of soft tissue sarcoma will be improved with the addition of PD-1 and CTLA-4 inhibition to cabozantinib, and that cabozantinib priming will increase the response to nivolumab and ipilimumab.

Trial Arms

NameTypeDescriptionInterventions
Cohort A: CabozantinibExperimentalPatients randomized to Cohort A will take cabozantinib at a dose of 60 mg by mouth once each day of each 28-day cycle. At time of progression, patients will continue on cabozantinib daily but will reduce their dose to 40 mg. They will cross over into Cohort B and initiate treatment.
  • Cabozantinib
Cohort B: Cabozantinib + Nivolumab + IpilimumabExperimentalPatients randomized to Cohort B will take cabozantinib at a dose of 40 mg by mouth once each day. Nivolumab will given IV at a dose of 3 mg/kg over approximately 30 minutes every 3 weeks for 4 doses, followed by 480 mg over approximately 30 minutes every 4 weeks until treatment discontinuation. Ipilimumab will be given IV at a dose of 1 mg/kg over approximately 90 minutes every 3 weeks for 4 doses. Participants who cross-over from Cohort A into Cohort B They will cross over into Cohort B will initiate treatment with nivolumab at a dose of 3 mg/kg IV over approximately 30 minutes and ipilimumab at a dose of 1 mg/kg IV over approximately 90 minutes. Nivolumab and ipilimumab will be given every 3 weeks for 4 doses. Nivolumab will then be continued at a dose of 480 mg IV over approximately 30 minutes every 4 weeks, with cabozantinib to continue at 40 mg every day.
  • Cabozantinib
  • Nivolumab
  • Ipilimumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically or cytologically confirmed metastatic or unresectable soft tissue
             sarcoma.

          -  Measurable disease defined as lesions that can be accurately measured in at least one
             dimension (longest diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by
             chest x-ray, or ≥ 10 mm with calipers by clinical exam.

          -  Refractory to at least one and no more than two lines of therapy.

          -  At least 18 years of age.

          -  ECOG performance status ≤ 1

          -  Normal bone marrow and organ function as defined below:

               -  Absolute neutrophil count ≥ 1,500/mm3 without granulocyte colony-stimulating
                  factor support

               -  White blood cell count ≥ 2,000/mm3

               -  Platelets ≥ 100,000/mm3 without transfusion

               -  Hemoglobin ≥ 9.0 g/dL

               -  Total bilirubin ≤ 1.5 x IULN (for subjects with Gilbert's disease, ≤ 3.0 x IULN)

               -  AST(SGOT), ALT(SGPT), and alkaline phosphatase (ALP) ≤ 3.0 x IULN; ALP ≤ 5.0 x
                  IULN with documented bone metastases

               -  Serum albumin ≥ 2.8 g/dl.

               -  Serum creatinine ≤ 1.5x IULN or calculated creatinine clearance ≥ 40 mL/min by
                  MDRD

               -  Urine protein/creatinine ration (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)

               -  PT/INR or PTT < 1.3 x IULN (within 7 days before first dose of study treatment)

          -  Corrected QT interval calculated by the Fridericia formula (QTcF) ≤ 500 ms (by ECG
             within 28 days before the first dose of study treatment).

          -  Recover to baseline or ≤ grade 1 from toxicities related to any prior treatments,
             unless AE(s) are clinically non-significant and/or stable on supportive therapy.

          -  The effects of cabozantinib on the developing human fetus are unknown. For this
             reason, women of childbearing potential and men must agree to use adequate
             contraception (hormonal or barrier method of birth control, abstinence) prior to study
             entry, for the duration of study participation, and for 5 months after the last dose
             of study treatment. Should a woman become pregnant or suspect she is pregnant while
             participating in this study, she must inform her treating physician immediately. Men
             treated or enrolled on this protocol must also agree to use adequate contraception
             prior to the study, for the duration of the study, and for at least 7 months after the
             last dose of study treatment.

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document (or that of legally authorized representative, if applicable).

        Exclusion Criteria:

          -  Translocation-driven sarcoma except for ASPS

          -  Previous treatment with cabozantinib or a PD-1 inhibitor, PD-L1 inhibitor, or CTLA-4
             inhibitor.

          -  A history of other malignancy with the exception of malignancies for which all
             treatment was completed at least 2 years before registration and the patient has no
             evidence of disease. Exceptions include basal cell or squamous cell carcinoma of the
             skin which were treated with local resection only or carcinoma in situ of the cervix,
             or other tumors discussed with the study PI.

          -  Currently receiving any other investigational agents.

          -  Known brain metastases. Patients with known brain metastases must be excluded from
             this clinical trial because of their poor prognosis and because they often develop
             progressive neurologic dysfunction that would confound the evaluation of neurologic
             and other adverse events.

          -  Receipt of any type of small molecule kinase inhibitor (including investigational
             kinase inhibitor) within 2 weeks before first dose of study treatment.

          -  Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy
             (including investigational) within 4 weeks before first dose of study treatment.

          -  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). Allowed anticoagulants are 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 subjects without known brain metastases who
                  are on a stable dose of the anticoagulant for at least 1 week before first dose
                  of study treatment without clinically significant hemorrhagic complications from
                  the anticoagulation regimen or the tumor.

          -  Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy
             within 4 weeks before first dose of study treatment. Systemic treatment with
             radionuclides within 6 weeks before the first dose of study treatment. Subjects with
             clinically relevant ongoing complications from prior radiation therapy are not
             eligible.

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to cabozantinib, nivolumab, ipilimumab, or other agents used in
             the study.

          -  Inability to swallow tablets.

          -  The subject has uncontrolled, significant intercurrent or recent illness including,
             but not limited to, the following conditions:

               -  Cardiovascular disorders:

                    -  Congestive heart failure New York Heart Association Class 3 or 4, unstable
                       angina pectoris, serious cardiac arrhythmias.

                    -  Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm
                       Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive
                       treatment.

                    -  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 of study
                       treatment.

                         -  Subjects with a diagnosis of incidental, subsegmental PE or DVT within
                            6 months are allowed if stable, asymptomatic, and treated with
                            anticoagulation for at least 1 week before first dose of study
                            treatment.

               -  Gastrointestinal (GI) disorders including those associated with a high risk of
                  perforation or fistula formation:

                    -  The subject has evidence of tumor invading the GI tract, active peptic ulcer
                       disease, inflammatory bowel disease (e.g., Crohn's disease), diverticulitis,
                       cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis,
                       acute obstruction of the pancreatic duct or common bile duct, or gastric
                       outlet obstruction.

                    -  Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal
                       abscess within 6 months before first dose.

                    -  Note: Complete healing of an intra-abdominal abscess must be confirmed
                       before first dose.

               -  Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon
                  (2.5 ml) of red blood, or other history of significant bleeding (eg, pulmonary
                  hemorrhage) within 12 weeks before first dose.

               -  Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
                  manifestation.

               -  Lesions invading or encasing any major blood vessels.

               -  Other clinically significant disorders that would preclude safe study
                  participation.

                    -  Serious non-healing wound/ulcer/bone fracture.

                    -  Uncompensated/symptomatic hypothyroidism.

                    -  Moderate to severe hepatic impairment (Child-Pugh B or C)

          -  Any active, known, or suspected autoimmune disease Note: subjects with type I diabetes
             mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as
             vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not
             expected to recur in the absence of an external trigger are permitted to enroll.

          -  Any condition requiring systemic treatment with either corticosteroids (> 10 mg daily
             prednisone equivalent) or other immunosuppressive medications within 14 days of
             randomization Note: inhaled, intranasal, intra-articular, or topical steroids are
             permitted. Adrenal replacement steroid doses > 10 mg daily prednisone equivalent are
             permitted in the absence of active autoimmune disease. Transient short-term use of
             systemic corticosteroids for allergic conditions (e.g. contrast allergy) is also
             allowed.

          -  Active infection requiring systemic treatment. Acute or chronic hepatitis B or C
             infection, known human immunodeficiency virus (HIV) or acquired immunodeficiency
             syndrome (AIDS)-related illness, or known positive test for tuberculosis infection

          -  History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
             pneumonitis, or evidence of active pneumonitis on screening chest CT scan

          -  Malabsorption syndrome

          -  Requirement for hemodialysis or peritoneal dialysis

          -  History of solid organ or allogeneic stem cell transplant.

          -  Major surgery (e.g. GI surgery removal or biopsy of brain metastasis) within 8 weeks
             before first dose of study treatment. Complete wound healing from major surgery must
             have occurred 1 month before first dose and from minor surgery (e.g., simple excision,
             tooth extraction) at least 10 days before first dose. Patients with clinically
             relevant ongoing complications from prior surgery are not eligible.

          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative
             pregnancy test within 15 days of study entry. Women of childbearing potential are
             defined as premenopausal females capable of becoming pregnant (i.e., females who have
             had any evidence of menses in the past 12 months, with the exception of those who had
             prior hysterectomy). However, women who have been amenorrheic for 12 or more months
             are still considered to be of childbearing potential if the amenorrhea is possibly due
             to prior chemotherapy, antiestrogens, low body weight, ovarian suppression, or other
             reasons

          -  Administration of a live, attenuated vaccine within 30 days prior to randomization.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Radiographic response rate by RECIST 1.1
Time Frame:Through end of treatment (estimated to be 24 months)
Safety Issue:
Description:Response rate = proportion of participants who achieve complete response or partial response Complete response: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Partial response: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.

Secondary Outcome Measures

Measure:Clinical benefit rate
Time Frame:Through end of treatment (estimated to be 24 months)
Safety Issue:
Description:-A confirmed clinical benefit is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 4 weeks apart or a confirmed SD at two consecutive tumor assessments at least 3 months apart. The CBR will be estimated by the number of patients with confirmed clinical benefit divided by the total number of evaluable patients
Measure:Progression-free survival
Time Frame:Through 5 years
Safety Issue:
Description:PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first. Progressive disease: Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. Unequivocal progression should not normally trump target lesion status. It must be representative of overall disease status change, not a single lesion increase. Patients will be censored at time of subsequent treatment regardless of response
Measure:Overall survival
Time Frame:Through 5 years
Safety Issue:
Description:Defined as from date of treatment start to date of death or date of last follow up if alive Patients will be censored at time of subsequent treatment regardless of response
Measure:Response rate to ipilimumab + nivolumab after cabozantinib priming
Time Frame:Through end of treatment (estimated to be 24 months)
Safety Issue:
Description:Response rate = proportion of participants who achieve complete response or partial response Complete response: Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). Partial response: At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters.
Measure:Change in quality of life as measured by FACT-G7
Time Frame:Baseline, day 1 of each cycle (each cycle is 4 weeks), and at time of disease progression (estimated to be up to 5 years)
Safety Issue:
Description:7 statements with answers ranging from 0=Not at all to 4=Very much. The higher the score, the better the quality of life The sum of the item scores will be multiplied by the number of items in the subscale then divided by the number of items answered. This will produce the total score.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Washington University School of Medicine

Last Updated

September 16, 2020