A Phase II Trial of Sunitinib and Nivolumab for KIT-mutated Advanced Melanoma

NCT02400385

Last updated date
Study Location
California Pacific Medical Center Research Institute
San Francisco, California, 94115, United States
Contact
1-800-718-1021

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Eligibility Criteria
condition
The disease, disorder, syndrome, illness, or injury that is being studied.
Melanoma
Sex
Females and Males
Age
Pediatric Trials: 0-17 Years
Adult Trials: 18+ Years
18 + years
Inclusion Criteria
The factors, or reasons, that allow a person to participate in a clinical study.
Show details

1. Unresectable stage 3 or stage 4 metastatic melanoma

2. A mutation, translocation, or fusion in the KIT gene in the patient's tumor felt to be potentially sensitive to tyrosine kinase inhibition. Expression of CD113 or other immunohistochemical test will not by itself satisfy this requirement.

3. Evidence of measurable disease by RECIST criteria 1.2 Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable. .

4. Resolution of all acute toxic effects of prior radiotherapy or surgical procedures to NCI CTCAE Version 3.0 grade ≤1.

5. Adequate organ function as defined by the following criteria:

- Absolute neutrophil count (ANC) ≥1,000/µL

- Platelets ≥75,000/µL

- Hemoglobin ≥8.0 g/dL

- Serum calcium ≤12.0 mg/dL

- Serum creatinine ≤1.5 x ULN

- Total serum bilirubin ≤1.5 x ULN

- Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ≤2.5 x local laboratory upper limit of normal (ULN), or AST and ALT ≤5 x ULN if liver function abnormalities are due to underlying malignancy

6. Karnofsky performance status > 60 %.

7. Male or female, 18 years of age or older.

8. Signed and dated informed consent document indicating that the subject (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to undergoing study screening procedures.

9. Subject's willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria
The factors, or reasons, that prevent a person from participating in a clinical study.
Show details


1. Brain metastasis requiring daily corticosteroid dosage over 7 .5mg/ day prednisone or
equivalent.


2. Prior therapy with sunitinib or anti-PD-1 or anti-PDL-1 antibodies (pembrolizumab,
nivolumab, etc.) Prior therapy with other KIT inhibitors (dasatinib, nilotinib,
imatinib, etc.) allowed but results from these patients will be analyzed separately.


3. Major surgery or radiation therapy within 2 weeks of starting the study treatment.
Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is
at least one measurable lesion that has not been irradiated.


4. NCI CTCAE Version 3.0 grade 3 hemorrhage within 4 weeks of starting the study
treatment.


5. Any of the following within the 4 months prior to study drug administration:
myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
graft, symptomatic heart failure, or cerebrovascular accident.


6. Ongoing cardiac dysrhythmias of NCI CTCAE Version 3.0 grade > 2.


7. Prolonged QTc interval on baseline EKG (>450 msec for males or >470 msec for females)


8. Uncontrolled hypertension (> 170/100 mm hg despite optimal medical therapy).


9. Concurrent treatment on another clinical trial. Supportive care trials or
non-treatment trials, e.g., QOL, are allowed.


10. Concomitant treatment with a drug having proarrhythmic potential (terfenadine,
quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol,
risperidone, indapamide and flecainide)


11. Use of potent CYP3A4 inhibitors and inducers 7 and 12 days before dosing, respectively
(see below).


12. Definite history of ulcerative colitis or Crohn's disease or lupus


13. History of allogeneic transplant.


14. Pregnancy or breastfeeding. Female subjects must be surgically sterile or be
postmenopausal, or must agree to use effective contraception during the period of
therapy. All female subjects with reproductive potential must have a negative
pregnancy test (serum or urine) prior to enrollment.

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Advanced Information
Descriptive Information
Brief Title  ICMJE A Phase II Trial of Sunitinib and Nivolumab for KIT-mutated Advanced Melanoma
Official Title  ICMJE A Phase II Trial of Sunitinib and Nivolumab for KIT-mutated Advanced Melanoma
Brief Summary This will be a phase II trial of the combination of sunitinib and nivolumab in patients with advanced, measurable, metastatic melanoma who harbor mutations in the KIT gene in their tumors. It is a multi-center trial using the FDA-approved doses of both sunitinib and nivolumab. Sunitinib will be provided by Pfizer. Endpoint is RECIST response rate and PFS.
Detailed Description

Curtin and Bastian in 2006 first described KIT mutations in melanoma. Although uncommon in non-acral cutaneous melanoma, these mutations are frequent in mucosal and acral melanomas. The KIT mutations in melanoma are similar to the KIT mutations in gastrointestinal intestinal stromal sarcomas (GIST) and these are believed to be driver mutations. In melanomas these mutations occur in an exclusive pattern in tumors without NRAS, BRAF, or GNAQ mutations. There is evidence that stage four melanoma patients with KIT mutations have a worse prognosis than other patients with similar stage and primary site.

Both imatinib and sunitinib are FDA approved for treatment of patients with GIST; these and other oral tyrosine kinase KIT inhibitors have been studied in melanoma patients with KIT mutations. Imatinib is the best studied with objective responses in 20% of patients in a multicenter trial, considerably lower than the efficacy seen in GIST. Sunitinib has the theoretical advantage of anti-angiogenic activity as well as anti -KIT activity and demonstrated objective responses in three of four patients in a small trial sponsored by Pfizer.(see citation).

Immunotherapy has a major role in the treatment of metastatic melanoma, with the approval and use of both Interleukin-2 and ipilimumab because of the ability of immunotherapy to produce durable responses and prolonged survival in a minority, but a significant number, of patients . Both sunitinib and ipilimumab have intestinal perforation as an unusual but very significant toxicity, which argues against using those two agents in combination. The anti-PD-1 antibody Nivolumab, however, is an immunologic agent that yields rapid and durable responses in melanoma with less colitis and less risk of intestinal perforation than ipilimumab. Nivolumab was FDA approved in December 2014 and NCCN guidelines include it as a first-line option.

Combining KIT receptor inhibition with sunitinib with immunotherapy with Nivolumab is an attractive investigational approach as the combination should produce complementary and perhaps synergistic efficacy.

Asim et al reported at ASCO in June 2014 a phase one study of sunitinib and nivolumab for the treatment of metastatic renal cell cancer. Sunitinib (50 mg/day x 4 week, off 2 weeks and nivolumab at 2mg/kg or 5mg/kg q 3 weeks was administered to 33 patients. No dose-limiting toxicities were seen but grade 3-4 AEs were seen in 24 of 33 patients. The most common AEs were elevated ALT (18%), hypertension (15%) and hyponatremia (15%). Objective responses sere seen in 52% (17/33) indicating an "encouraging activity and a manageable safety profile" in patients with renal cell cancer. The Nivolumab dose of 5mg/kg Q 3 weeks (1.67mg/kg/week) on that study is slightly above the usual dose of 3mg/kg Q 2 weeks (1.5mg/kg/week).

Study Design:

This is an open-label multi-center phase 2 study of sunitinib and Nivolumab in combination in patients with KIT mutated metastatic melanoma. Study to begin after FDA approval of nivolumab Total number of study subjects will be approximately 12-18 patients.

Objectives

Primary objective:

  1. To describe the preliminary clinical efficacy of sunitinib when given in combination with nivolumab to patients with KIT-mutated melanoma
  2. To describe the immunologic effects of sunitinib when administered in combination with Nivolumab

Co-primary endpoints:

  1. Objective response using RECIST 1.1 immune modified response criteria
  2. Progression-free survival using immune-modified response criteria

Secondary endpoints:

  1. Toxicities using CTAE criteria
  2. Changes in peripheral blood total lymphocyte counts and T and B cell count
  3. Overall survival The trial is sponsored by the California Pacific Medical Center Research Institute and the sunitinib will be provided by Pfizer. Commercial sources will be used for the nivolumab, whose use is in accord with NCCN guidelines.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Melanoma
Intervention  ICMJE
  • Drug: sunitinib
    sunitinib 50mg/day po, 4 weeks on 2 weeks off
    Other Name: Sutent
  • Drug: nivolumab
    nivolumab 3mg/kg IV ever 2 weeks
    Other Name: Opdivo
Study Arms  ICMJE Experimental: Treatment
Sunitinib 50mg/day, 4 weeks on and 2 weeks off, and concurrent nivolumab 3mg/kg iv every 2 weeks, both for three years if tolerated.
Interventions:
  • Drug: sunitinib
  • Drug: nivolumab
Publications * Minor DR, Kashani-Sabet M, Garrido M, O'Day SJ, Hamid O, Bastian BC. Sunitinib therapy for melanoma patients with KIT mutations. Clin Cancer Res. 2012 Mar 1;18(5):1457-63. doi: 10.1158/1078-0432.CCR-11-1987. Epub 2012 Jan 18.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Withdrawn
Actual Enrollment  ICMJE
 (submitted: January 30, 2017)
0
Original Estimated Enrollment  ICMJE
 (submitted: March 23, 2015)
18
Actual Study Completion Date  ICMJE December 2015
Actual Primary Completion Date December 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Unresectable stage 3 or stage 4 metastatic melanoma
  2. A mutation, translocation, or fusion in the KIT gene in the patient's tumor felt to be potentially sensitive to tyrosine kinase inhibition. Expression of CD113 or other immunohistochemical test will not by itself satisfy this requirement.
  3. Evidence of measurable disease by RECIST criteria 1.2 Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable. .
  4. Resolution of all acute toxic effects of prior radiotherapy or surgical procedures to NCI CTCAE Version 3.0 grade ?1.
  5. Adequate organ function as defined by the following criteria:

    • Absolute neutrophil count (ANC) ?1,000/µL
    • Platelets ?75,000/µL
    • Hemoglobin ?8.0 g/dL
    • Serum calcium ?12.0 mg/dL
    • Serum creatinine ?1.5 x ULN
    • Total serum bilirubin ?1.5 x ULN
    • Serum aspartate transaminase (AST; serum glutamic oxaloacetic transaminase [SGOT]) and serum alanine transaminase (ALT; serum glutamic pyruvic transaminase [SGPT]) ?2.5 x local laboratory upper limit of normal (ULN), or AST and ALT ?5 x ULN if liver function abnormalities are due to underlying malignancy
  6. Karnofsky performance status > 60 %.
  7. Male or female, 18 years of age or older.
  8. Signed and dated informed consent document indicating that the subject (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to undergoing study screening procedures.
  9. Subject's willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

  1. Brain metastasis requiring daily corticosteroid dosage over 7 .5mg/ day prednisone or equivalent.
  2. Prior therapy with sunitinib or anti-PD-1 or anti-PDL-1 antibodies (pembrolizumab, nivolumab, etc.) Prior therapy with other KIT inhibitors (dasatinib, nilotinib, imatinib, etc.) allowed but results from these patients will be analyzed separately.
  3. Major surgery or radiation therapy within 2 weeks of starting the study treatment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one measurable lesion that has not been irradiated.
  4. NCI CTCAE Version 3.0 grade 3 hemorrhage within 4 weeks of starting the study treatment.
  5. Any of the following within the 4 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic heart failure, or cerebrovascular accident.
  6. Ongoing cardiac dysrhythmias of NCI CTCAE Version 3.0 grade > 2.
  7. Prolonged QTc interval on baseline EKG (>450 msec for males or >470 msec for females)
  8. Uncontrolled hypertension (> 170/100 mm hg despite optimal medical therapy).
  9. Concurrent treatment on another clinical trial. Supportive care trials or non-treatment trials, e.g., QOL, are allowed.
  10. Concomitant treatment with a drug having proarrhythmic potential (terfenadine, quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide and flecainide)
  11. Use of potent CYP3A4 inhibitors and inducers 7 and 12 days before dosing, respectively (see below).
  12. Definite history of ulcerative colitis or Crohn's disease or lupus
  13. History of allogeneic transplant.
  14. Pregnancy or breastfeeding. Female subjects must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. All female subjects with reproductive potential must have a negative pregnancy test (serum or urine) prior to enrollment.
Sex/Gender  ICMJE
Sexes Eligible for Study:All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02400385
Other Study ID Numbers  ICMJE 703131-1
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD:No
Responsible Party California Pacific Medical Center Research Institute
Study Sponsor  ICMJE California Pacific Medical Center Research Institute
Collaborators  ICMJE Pfizer
Investigators  ICMJE
Study Chair:David R Minor, M.D.California Pacific Medical Center Research Institute
Principal Investigator:Kevin B Kim, MDCalifornia Pacific Melanoma Center
PRS Account California Pacific Medical Center Research Institute
Verification Date September 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP