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A Phase II of Nivolumab Plus Ipilimumab in Non-resectable Sarcoma and Endometrial Carcinoma

NCT02982486

Description:

The purpose of this study is to determine whether nivolumab plus ipilimumab are effective and safe in the treatment of sarcoma and endometrial carcinoma patients with somatic deficient MMR as a selection tool.

Related Conditions:
  • Bone Sarcoma
  • Endometrial Carcinoma
  • Endometrial Clear Cell Adenocarcinoma
  • Endometrial Serous Adenocarcinoma
  • Endometrioid Adenocarcinoma
  • Ovarian Endometrioid Adenocarcinofibroma
  • Ovarian Endometrioid Adenocarcinoma
  • Ovarian Endometrioid Tumor
  • Soft Tissue Sarcoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Phase II of Nivolumab Plus Ipilimumab in Non-resectable Sarcoma and Endometrial Carcinoma
  • Official Title: A Phase II Single Arm Study Assessing Efficacy & Safety of Nivolumab Plus Ipilimumab in Nonresectable/Metastatic Sarcoma and Endometrial Carcinoma Patients With Somatic Deficient MMR as a Selection Tool

Clinical Trial IDs

  • ORG STUDY ID: 0239/16
  • NCT ID: NCT02982486

Conditions

  • Soft Tissue Sarcoma
  • Bone Sarcoma
  • Chondrosarcoma
  • Gastrointestinal Stromal Sarcoma
  • Ewing's Tumor Metastatic
  • Ewing's Tumor Recurrent
  • Osteosarcoma
  • Desmoplastic Small Round Cell Tumor

Interventions

DrugSynonymsArms
Ipilimumabanti CTLA4Nivolumab and ipilimumab
NivolumabAnti PD-1Nivolumab and ipilimumab

Purpose

The purpose of this study is to determine whether nivolumab plus ipilimumab are effective and safe in the treatment of sarcoma and endometrial carcinoma patients with somatic deficient MMR as a selection tool.

Detailed Description

      The expected duration of this study is 36 months (18 months accrual period and 18 month
      follow up period). Enrollment into the screening or treatment phase of the study will be
      stopped when the actual subject numbers have been achieved.

      This single arm single institution, open label, prospective, phase II trial will evaluate the
      efficacy and safety of Nivolumab 240 mg IV every 2 weeks plus ipilimumab 1 mg/kg every 6
      weeks in patients with nonresectable/metastatic sarcoma or endometrial carcinoma with somatic
      deficient MMR as a selection tool.patients. Number of patients in the study will reflect the
      reconciliation between statistical requirements and incidence.

      Treatment will continue until disease progression, development of unacceptable toxicity,
      noncompliance or withdrawal of consent by the patient or investigator decision.

      All screening requirements must be completed within 28 days of the visit (except for Patients
      will be examined on cycle 1 day-1 and every 2 weeks, including complete blood count (CBC) and
      chemistry, until disease progression. CT/MRI imaging (contrast) will be performed every 6
      weeks for response evaluation for the first 48 weeks and every 12 weeks thereafter. Clinical
      benefit as well as individual categories of response (complete response (CR), partial
      response (PR), stable disease (SD) and progressive disease (PD) will be determined using
      Response Evaluation Criteria in Solid Tumors 1.1 (RECIST). Response duration endpoints,
      including median PFS, PFS at 12 and 24 weeks and OS will be assessed using the Kaplan-Meier
      method. Toxicity (AEs) will be recorded using the NCI- Common Toxicity Criteria for Adverse
      Effects v 4.03 (NCI-CTCAE). Screening procedures will include immunostaining for MLH1, MSH2,
      MSH6 and PMS2 all performed on formalin fixed paraffin embedded (FFPE) tissue sections. In
      addition tumor DNA, extracted from FFPE tissue (after choosing optimal area by a
      Pathologist), will be submitted to FoundationOne for a later exploratory analysis.
    

Trial Arms

NameTypeDescriptionInterventions
Nivolumab and ipilimumabExperimentalNivolumab 240 mg IV every 2 weeks plus Ipilimumab 1 mg/m2 IV every 6 weeks
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          1. Patients will sign the informed consent form before the initiation of any study
             procedure.

          2. Males and Females, 18 years or older

          3. Patients must have a FFPE tumor block, one representative hematoxylin and eosin (H&E)
             and 20 unstained sarcoma/endometrial carcinoma tissue slides available for submission
             to pathology review; this step is mandatory prior to registration to confirm
             eligibility.

          4. Tumors must immune-stain negatively to one or more of the following proteins: MLH1,
             MSH2, MSH6 and PMS2

          5. Patients must have histologically confirmed bone or soft tissue sarcoma by pathology
             review or a diagnosis of FIGO grade 3 endometrioid cancer, serous, clear cell, or
             mixed high grade endometrial cancer.

          6. Measurable disease of sarcoma or endometrial carcinoma defined as lesions that can be
             accurately measured in at least one dimension (longest diameter to be recorded) as >10
             mm with CT scan or MRI, as >20 mm by chest x-ray, or >10 mm with calipers by clinical
             exam by RECIST 1.1.

          7. Locally advanced non-operable or metastatic disease

          8. >= 1 prior systemic therapy for sarcoma or endometrial carcinoma, including adjuvant
             systemic therapy

          9. No treatment with biologic therapy, immunotherapy, chemotherapy, investigational agent
             for malignancy =< 21 days before study registration

         10. Eastern Cooperative Oncology Group ECOG performance status 0 or 1

         11. Screening laboratory values must meet the following criteria and should be obtained
             within 14 days prior to first drug dose

               -  WBC ≥ 2000/μL

               -  Neutrophils ≥ 1500/μL

               -  Platelets ≥ 100 x103/μL

               -  Hemoglobin > 9.0 g/dL

               -  Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using
                  the Cockcroft-Gault formula below):

                    -  Female CrCl = (140 - age in years) x weight in kg x 0.85

                       72 x serum creatinine in mg/dL

                    -  Male CrCl = (140 - age in years) x weight in kg x 1.00

                       72 x serum creatinine in mg/dL

               -  AST/ALT ≤ 3 x ULN

               -  Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have
                  total bilirubin < 3.0 mg/dL)

               -  Serum electrolytes: baseline serum potassium > 3.5 mmol/L (potassium
                  supplementation may be given to restore the serum potassium above this level
                  prior to study entry)

               -  Thyroid stimulating hormone (TSH) within normal limits (WNL); supplementation is
                  acceptable to achieve a TSH WNL; in patients with abnormal TSH if free T4 is
                  normal and patient is clinically euthyroid, patient is eligible

         12. Patients should have resolution of any toxic effects of prior therapy (except
             alopecia) to NCI CTCAE, version 4.0, grade 1 or less

         13. Patients may be re-screened and re-enrolled in the study if they failed screening or
             were enrolled but did not receive study drugs in this case they will have to sign a
             new informed concent form.

         14. Palliative (limited-field) radiation therapy is permitted, if all of the following
             criteria are met:

               -  Repeat imaging demonstrates no new sites of bone metastases.

               -  The lesion being considered for palliative radiation is not a target lesion.

         15. A negative pregnancy test (a negative serum or urine pregnancy test (minimum
             sensitivity 25 IU/L or equivalent units of HCG)) done =< 7 days prior to the start of
             study drug.

         16. Women of childbearing potential (WOCBP) must use appropriate method(s) of
             contraception. WOCBP should use an adequate method to avoid pregnancy for 5 months (30
             days plus the time required for nivolumab to undergo five half-lives) after the last
             dose of investigational drug

         17. Women of childbearing potential must have a negative serum or urine pregnancy test
             (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the
             start of nivolumab

         18. Women must not be breastfeeding

         19. Men who are sexually active with WOCBP must use any contraceptive method with a
             failure rate of less than 1% per year. Men receiving nivolumab and who are sexually
             active with WOCBP will be instructed to adhere to contraception for a period of 7
             months after the last dose of investigational product Women who are not of
             childbearing potential (ie, who are postmenopausal or surgically sterile as well as
             azoospermic men do not require contraception

        Exclusion Criteria:

          1. Active, known or suspected autoimmune disease. Subjects 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

          2. 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.

          3. FIGO grade 1 or 2 endometrioid cancer.

          4. Have had prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4
             antibody, or any other antibody or drug specifically targeting T-cell costimulation or
             immune checkpoint pathways

          5. Prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2
             weeks prior to the first dose of nivolumab/ipilimumab or has not recovered (i.e., to ≤
             grade 1 or baseline) from adverse events due to a previously administered agent. Note,
             subjects with ≤ grade 2 neuropathy are an exception to this criterion and may qualify
             for the study. Note, if a subject received major surgery, she must have recovered
             adequately from the toxicity and/or complications from the intervention prior to
             starting therapy.

          6. No known or suspected allergy to nivolumab or study drug components and no history of
             severe hypersensitivity reaction to any monoclonal antibody

          7. Active brain metastases or leptomeningeal metastases. Subjects with brain metastases
             are eligible if metastases have been treated and there is no magnetic resonance
             imaging (MRI) evidence of progression for at least 4 weeks after treatment is complete
             and within 28 days prior to the first dose of nivolumab administration. There must
             also be no requirement for immunosuppressive doses of systemic corticosteroids (> 10
             mg/day prednisone equivalents) for at least 2 weeks prior to study drug
             administration.

          8. As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab
             combinations, drugs with a predisposition to hepatoxicity should be used with caution
             in patients treated with nivolumab-containing regimen.

          9. Have a positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C
             virus ribonucleic acid (HCV antibody) indicating acute or chronic infection

         10. Have known history of testing positive for human immunodeficiency virus (HIV) or known
             acquired immunodeficiency syndrome (AIDS)

         11. Known active pulmonary disease with hypoxia defined as:

             Oxygen saturation < 85% on room air or Oxygen saturation < 88% despite supplemental
             oxygen

         12. Pregnant and nursing women

         13. Eastern Cooperative Oncology Group (ECOG) performance status 3-4

         14. Prior malignancy active within the previous 3 years except for locally curable cancers
             that have been apparently cured, such as basal or squamous cell skin cancer,
             superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response to therapy as evaluated by RECIST 1.1
Time Frame:36 months
Safety Issue:
Description:complete and partial response

Secondary Outcome Measures

Measure:Median Progression-free survival (PFS)
Time Frame:36 months
Safety Issue:
Description:PFS will be computed from the date of start of treatment to the first documented date of progression or the date of death, due to any cause assessed by investigator.
Measure:Progression-free survival (PFS) assessed at 12 weeks
Time Frame:12 weeks
Safety Issue:
Description:PFS will be computed from the date of start of treatment to week 12 as assessed by investigator.
Measure:Progression-free survival (PFS) assessed at 24 weeks
Time Frame:24 weeks
Safety Issue:
Description:PFS will be computed from the date of start of treatment to week 24 as assessed by investigator
Measure:overall survival
Time Frame:36 months
Safety Issue:
Description:will be computed from the date of start of treatment to the date of death, due to any cause. Patients alive or lost for follow-up at the time of the analysis will be censored at the date of last follow-up.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Assaf-Harofeh Medical Center

Trial Keywords

  • nivolumab
  • ipilimumab
  • immunotherapy
  • PD-1 inhibitor
  • sarcoma

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