Clinical Trials /

Neoadjuvant and Adjuvant Checkpoint Blockade

NCT02519322

Description:

This randomized phase II trial studies how well nivolumab with or without ipilimumab or relatlimab before surgery works in treating patients with stage IIIB-IV melanoma that can be removed by surgery. Immunotherapy with monoclonal antibodies, such as nivolumab, ipilimumab, and relatlimab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving nivolumab alone or in combination with ipilimumab or relatlimab before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Neoadjuvant and Adjuvant Checkpoint Blockade in Patients With Clinical Stage III or Oligometastatic Stage IV Melanoma
  • Official Title: Neoadjuvant and Adjuvant Checkpoint Blockade in Patients With Clinical Stage III or Oligometastatic Stage IV Melanoma

Clinical Trial IDs

  • ORG STUDY ID: 2015-0041
  • SECONDARY ID: NCI-2015-01520
  • NCT ID: NCT02519322

Conditions

  • Melanoma
  • Oligometastatic Melanoma

Interventions

DrugSynonymsArms
Nivolumab 1mg/kgBMS-936558, OpdivoGroup B - Nivolumab + Ipilimumab
IpilimumabYervoy, BMS-734016, MDX010Group B - Nivolumab + Ipilimumab
Nivolumab 3 mg/kgBMS-936558, OpdivoGroup A - Nivolumab

Purpose

The goal of this clinical research study is to learn if giving nivolumab alone or in combination with ipilimumab before and after surgery can help to control metastatic melanoma. The safety of these drugs will also be studied.

Detailed Description

      Study Groups:

      If you are found to be eligible to take part in this study, you will be randomly assigned
      (as in the flip of a coin) to 1 of 2 study groups. This is done because no one knows if one
      study group is better, the same, or worse than the other group. You will have an equal (1 in
      2) chance of being assigned to either of the groups:

        -  If you are in Group A, you will receive nivolumab every 2 weeks (+/- 7 days) for a
           total of 4 doses and then you will have surgery. After that, you will receive nivolumab
           for an additional 6 months.

        -  If you are in Group B, you will receive nivolumab (+/- 7 days) and ipilimumab every 3
           weeks for 3 doses and then you will have surgery. After that, you will receive
           nivolumab alone for 6 months.

      You and the study staff will know to which group you have been assigned.

      Study Drug Administration:

      If you are in Group A, you will receive nivolumab by vein over about 1 hour on Days 1, 15,
      29, and 43. You will then have surgery. After surgery, you will receive nivolumab by vein
      every 2 weeks (+/- 7 days) for 6 months (13 doses).

      If you are in Group B, you will receive nivolumab by vein over about 1 hour and ipilimumab
      by vein over about 90 minutes on Days 1, 22, and 43. You will then have surgery. After
      surgery, you will receive nivolumab by vein every 2 weeks (+/- 7 days) for 6 months (13
      doses).

      If treatment needs to be delayed more than two weeks because of safety reasons, the next
      dose(s) can be skipped. However, once you are able to begin treatment again and the disease
      appears to be responding, you can remain on the study and can proceed with surgery as
      planned.

      Study Visits:

      Group A Before Surgery:

      On Day 1:

        -  You will have a physical exam.

        -  Blood (about 3 ½ tablespoons) will be drawn for routine tests

      On Days 15 and 29:

        -  You will have a physical exam.

        -  Blood (about 6 ½ tablespoons) will be drawn for routine tests and for tests of the
           immune system.

        -  You will have a tumor biopsy for biomarker testing on Day 15. Biomarkers are found in
           blood and tissue and may be related to your reaction to the study drug.

      On Day 43:

        -  You will have a physical exam.

        -  Blood (about 3 ½ tablespoons) will be drawn for routine tests

      On Day 57:

        -  You will have an EKG.

        -  You will have a physical exam.

        -  Blood (about 6 ½ tablespoons) will be drawn for routine tests and tests of the immune
           system.

        -  You will have a CT scan, PET-CT scan, or MRI to check the status of the disease. If the
           doctor thinks the disease can still be removed through surgery, you will then have
           surgery in the following week. If the disease is no longer able to be treated with
           surgery, you will be taken off study. Your doctor will discuss other treatment options
           with you.

        -  If you can become pregnant, blood (about 1/2 teaspoon) or urine will be collected for
           pregnancy test.

      Group B Before Surgery:

      On Day 1:

        -  You will have a physical exam.

        -  Blood (about 6 ½ tablespoons) will be drawn for routine tests and for tests of the
           immune system.

      On Days 22 and 43:

        -  You will have a physical exam.

        -  Blood (about 6 ½ tablespoons) will be drawn for routine tests and for tests of the
           immune system.

        -  You will have a tumor biopsy for biomarker testing on Day 22.

      On Day 57:

        -  You will have an EKG.

        -  You will have a physical exam.

        -  Blood (about 6 ½ tablespoons) will be drawn for routine tests and for tests of the
           immune system.

        -  You will have a CT scan, PET-CT scan, or MRI to check the status of the disease. If the
           doctor thinks the disease can still be removed through surgery, you will then have
           surgery in the following week. If the disease is no longer able to be treated with
           surgery, you will be taken off study. Your doctor will discuss other treatment options
           with you.

        -  If you can become pregnant, blood (about 1/2 teaspoon) or urine will be collected for
           pregnancy test.

      Surgery (All Participants):

      On Day 57 you will have surgery to remove the disease. You will sign a surgery consent form
      that describes the procedure and its risks. Tissue will be collected at time of surgery for
      research to test for any remaining melanoma cells and to check the status of the disease.

      Study Visits After Surgery for All Participants:

      Every 2 weeks after you recover from surgery (every time you receive nivolumab):

        -  You will have a physical exam.

        -  Blood (about 3 ½ tablespoons) will be drawn for routine tests.

      At the following visits additional tests and procedures will be performed:

        -  At Weeks 10, 22, and 34 after surgery, blood (about 3 tablespoons) will also be drawn
           for tests of the immune system.

        -  At Weeks 22 and 34 after surgery, you will have a CT scan, PET-CT scan, or MRI to check
           the status of the disease.

      Length of Treatment:

      You may receive up to 13 doses of nivolumab after you have surgery. You will no longer be
      able to take the study drug(s) if the disease gets worse, if intolerable side effects occur,
      or if you are unable to follow study directions.

      Your participation on the study will be over after the follow-up visits.

      End-of-Treatment Visit:

      When you stop receiving nivolumab, or if you have an intolerable side effect, you will have
      an end-of-treatment visit. The following tests and procedures will be performed:

        -  You will have a physical exam.

        -  Blood (about 6 ½ tablespoons) will be drawn for routine tests and tests of the immune
           system.

        -  You will have a CT scan, PET-CT scan, or MRI to check the status of the disease.

      Follow-Up Visits:

      Every 12 weeks after your last dose of drug(s):

        -  You will have a physical exam.

        -  Blood (about 6 tablespoons) will be drawn for routine tests and for tests of the immune
           system.

        -  You will have a CT scan, PET-CT scan, or MRI to check the status of the disease.

      The study staff will contact you for follow-up, for up to 2 years after surgery. You will be
      asked about your health status, any anti-cancer therapy you receive (including radiation),
      and how the disease may be responding to therapy. If you need to stop receiving treatment
      early, the study staff will contact you to check you health status every 3 months until you
      start a new treatment for melanoma. This follow-up contact may be done in-person, if you
      continue treatment at MD Anderson. If not you will be contacted by phone, email or letter.

      This is an investigational study. Ipilimumab and nivolumab are FDA approved and commercially
      available to treat metastatic melanoma. It is investigational to give the drugs in
      combination before and after surgery. The study doctor can explain how the study drugs are
      designed to work.

      Up to 40 participants will be enrolled in this study. All will take part at MD Anderson.
    

Trial Arms

NameTypeDescriptionInterventions
Group A - NivolumabExperimentalNeoadjuvant phase: Nivolumab 3 mg/kg by vein every 2 weeks on weeks 1, 3, 5 and 7 prior to surgical excision. Adjuvant Phase: Nivolumab 3 mg/kg by vein every 2 weeks postoperatively for 6 months.
  • Nivolumab 3 mg/kg
Group B - Nivolumab + IpilimumabExperimentalNeoadjuvant Phase: Nivolumab 1 mg/kg by vein combined with Ipilimumab 3 mg/kg by vein every 3 weeks on weeks 1, 4 and 7 prior to surgical excision. Adjuvant Phase: Nivolumab 3 mg/kg by vein every 2 weeks postoperatively for 6 months.
  • Nivolumab 1mg/kg
  • Ipilimumab
  • Nivolumab 3 mg/kg

Eligibility Criteria

        Inclusion Criteria:

          1. Capable of giving written informed consent, which includes compliance with the
             requirements and restrictions listed in the consent form

          2. Patients must have histologically or cytologically confirmed Stage IIIB/C or Stage IV
             oligometastatic melanoma. Oligometastatic melanoma is defined as three or fewer areas
             of resectable disease excluding central nervous system and bone involvement. Patients
             with cutaneous, mucosal, acral, ocular or unknown primary melanomas are eligible for
             enrollment. For patients with stage IV disease with distant lymph nodes (stage M1a),
             a maximum of three separate lymph node sites fit the definition of oligometastatic
             disease. Resectable tumors are defined as having no significant vascular, neural or
             bony involvement. Only cases where a complete surgical resection with tumor-free
             margins can safely be achieved are defined as resectable.

          3. Patients will have at least one melanoma deposit that can undergo serial biopsy (at
             least 2 time points) during the neoadjuvant phase of the protocol. Patients must be
             willing to provide tumor samples at the time points specified in the Study Procedure
             Tables.

          4. All patients must undergo a baseline tumor biopsy for PD-L1 testing (PD-L1 positivity
             is determined by greater than or equal to 1% of cells staining in the membrane by
             immunohistochemistry). For patients with stage IV disease, site of tumor biopsy will
             preferably be from non-lymph node disease site. For PD-L1 testing, the biopsy should
             contain sufficient tumor content (>/=100 tumor cells/4-micron tissue section). If a
             sample contains insufficient tumor content, a re-biopsy will be required to obtain a
             sample with sufficient tumor content prior to treatment.

          5. Patients must be medically fit enough to undergo surgery as determined by the
             treating medical and surgical oncology team

          6. Patients who have been previously been treated in the adjuvant setting for melanoma
             (including use of prior interferon alpha, pegylated interferon or vaccine on clinical
             trial) will be eligible for treatment after a 28 day wash-out period

          7. Patients must have measurable disease, defined by RECIST 1.1

          8. Age >/= 18 years

          9. ECOG performance status 0-1

         10. Patients must have organ and marrow function as defined below: Hematologic Absolute
             neutrophil count (ANC) >/= 1.5 X 10^9/L; Hemoglobin >/= 9.5 g/dL Platelets >/= 100 X
             10^9/L PT/INR and PTT </= 1.5 X ULN. Hepatic Total bilirubin </= 1.5 X ULN (isolated
             bilirubin >1.5 X ULN is acceptable if bilirubin is fractionated and direct bilirubin
             <35%) AST and ALT Albumin </= 2.5 X ULN 1 >/=2.5 g/dL Renal Creatinine OR Calculated
             creatinine clearance OR 24-hour urine creatinine clearance </=1.5 X ULN 2 >/= 50
             mL/min >/= 50 mL/min

         11. Women are eligible to participate if: Non-childbearing potential defined as
             pre-menopausal females with a documented tubal ligation or hysterectomy; or
             postmenopausal defined as 12 months of spontaneous amenorrhea [in questionable cases
             a blood sample with simultaneous follicle stimulating hormone (FSH) > 40 MlU/mL and
             estradiol < 40 pg/mL (<140 pmol/L) is confirmatory]. Females on hormone replacement
             therapy (HRT) and whose menopausal status is in doubt will be required to use one of
             the contraception methods if they wish to continue their HRT during the study.
             Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status
             prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse
             between the cessation of therapy and the blood draw; this interval depends on the
             type and dosage of HRT.

         12. 11b) The individual methods of contraception and duration should be determined in
             consultation with the investigator. Women of childbearing potential (WOCBP) must
             follow instructions for birth control when the half-life of the investigational drug
             is greater than 24 hours, contraception should be continued for a period of 30 days
             plus the time required for the investigational drug to undergo five half-lives. The
             half-life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively.
             WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the
             time required for nivolumab to undergo five half-lives) after the last dose of
             investigational drug. WOCBP 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 investigational product.

         13. Women must not be breastfeeding

         14. Men who are sexually active with WOCBP must use any contraceptive method with a
             failure rate of less than 1% per year The investigator shall review contraception
             methods and the time period that contraception must be followed. Men who are sexually
             active with WOCBP must follow instructions for birth control when the half-life of
             the investigational drug is greater than 24 hours, contraception should be continued
             for a period of 90 days plus the time required for the investigational drug to
             undergo five half-lives. The half-life of nivolumab and ipilimumab is up to 25 days
             and 18 days, respectively. Therefore, men who are sexually active with WOCBP must
             continue contraception for 31 weeks (90 days plus the time required for nivolumab to
             undergo five half-lives) after the last dose of investigational drug.

         15. Women who are not of childbearing potential (i.e., who are postmenopausal or
             surgically sterile and azoospermic men do not require contraception.

        Exclusion Criteria:

          1. Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy,
             or biologic therapy) or investigational anti-cancer drug

          2. Any major surgery within the last 3 weeks

          3. Brain metastases, leptomeningeal disease or bone metastases

          4. Pregnant or lactating female

          5. Unwillingness or inability to follow the procedures required in the protocol

          6. Current use of anticoagulants (warfarin, heparin, direct thrombin inhibitors) at
             therapeutic levels

          7. Any serious or uncontrolled medical disorder that, in the opinion of the
             investigator, may increase the risk associated with study participation or study drug
             administration, impair the ability of the subject to receive protocol therapy, or
             interfere with the interpretation of study results.

          8. Prior malignancy active within the previous 2 years except for patient's prior
             diagnosis of melanoma and 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 with local control measures (surgery,
             radiation).

          9. Subjects with active, known or suspected autoimmune disease. Subjects with 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 are permitted
             to enroll.

         10. Subjects with 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.

         11. Prior treatment with an anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody

         12. Any positive test result for hepatitis B or C virus indicating acute or chronic
             infection

         13. Known history of testing positive for human immunodeficiency virus or known acquired
             immunodeficiency syndrome

         14. History of severe hypersensitivity reaction to any monoclonal antibody

         15. Prisoners or subjects who are involuntarily incarcerated

         16. Subjects who are compulsorily detained for treatment of either a psychiatric or
             physical (infection disease) illness
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Pathologic Response of Neoadjuvant Nivolumab in Participants with High-Risk Resectable Melanoma
Time Frame:Day 57
Safety Issue:
Description:Pathologic complete response (pCR) defined as the absence of any residual invasive malignant cells on hematoxylin and eosin evaluation of the resected melanoma specimen.

Secondary Outcome Measures

Measure:Immunologic Response of Neoadjuvant Nivolumab in Participants with High-Risk Resectable Melanoma
Time Frame:Baseline, Day 57, and 2 weeks after surgery
Safety Issue:
Description:Immunologic response determined by change in T cell infiltrate from baseline to on-treatment and surgical specimens in response to therapy.
Measure:Immunologic Response of Neoadjuvant Nivolumab and Ipilimumab Participants with High-Risk Resectable Melanoma
Time Frame:Baseline, Day 57, and 2 weeks after surgery
Safety Issue:
Description:Immunologic response determined by change in T cell infiltrate from baseline to on-treatment and surgical specimens in response to therapy.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Trial Keywords

  • Melanoma
  • Oligometastatic melanoma
  • Resectable
  • Nivolumab
  • BMS-936558
  • Opdivo
  • Ipilimumab
  • Yervoy
  • BMS-734016
  • MDX010

Last Updated

March 17, 2017