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Title A Multi-Center Phase 2 Open-Label Study to Evaluate Safety and Efficacy in Subjects with Melanoma Metastatic to the Brain treated with Nivolumab in Combination with Ipilimumab followed by Nivolumab Monotherapy

IRB BRMY1615

CC 041536C

Hospital Main Campus

Phase Phase 2

Disease Brain, Melanoma

Drug Ipilimumab, Nivolumab

Description

Primary Objective

• To assess clinical benefit rate (CBR, defined as complete response [CR] + partial response [PR] + stable disease [SD] > 6 months) in the brain in subjects with melanoma metastatic to the brain per modified RECIST 1.1 criteria.

Secondary Objectives

• To assess the systemic CBR defined as CR+PR+SD ≥ 6 months (assessed per modified RECIST 1.1)
• To assess OS
• To evaluate the brain-specific safety and tolerability of the combination regimen in patients with or without stereotactic radiotherapy (SRT) received prior to study entry, or while on study.

Exploratory Objectives

• To assess the global (brain plus systemic) CBR defined as CR+PR+SD ≥ 6 months in the brain plus systemic per modified RECIST 1.1
• To assess efficacy using NANO criteria
• To evaluate the overall safety and tolerability of the combination regimen in patients with or without stereotactic radiotherapy (SRT) received prior to study entry or on study
• To evaluate association between baseline pathologic features of primary cutaneous melanoma (eg, regression, ulceration, pattern and components of immune infiltrate) and CBR endpoints
• To explore potential biomarkers associated with clinical response to nivolumab combined with ipilimumab by analyzing tumor tissue specimens for proteins including, but not limited to, PD-1, PD-L1, and other markers related to immune cell populations involved in regulating immune responses in comparison to clinical outcomes
• To evaluate association between BRAF/NRAS mutation status and response endpoints
• To compare tissue biomarker profiles between paired tissues from systemic and brain metastases from individual patients, where available; if possible this analysis will also be applied for sample sets that include a primary, an systemic metastasis and a brain metastasis from the same patient
• To assess peripheral blood immune cell subpopulations (which may include but is not limited to CD4+ T-cell, CD8+ T-cell, Treg, NK, B-cell, MDSC, activated T-cells, memory/exhausted T cells) and serum soluble factors with changes in post-treatment profiles as they relate to clinical endpoints and/or the occurrence of adverse events
• To assess the effects of natural genetic variation (SNPs) in select genes including, but not limited to, PD-1, PD-L1, PD-L2, and CTLA-4 on clinical endpoints and/or on the occurrence of adverse events
• To estimate the incidence of MRI-defined brain edema, hemorrhage, and increase in tumor size before regression (pseudoprogression) in the brain metastases and to evaluate any association with the onset and/or CBR observed in the brain or system
• To compare computer-assisted tumor volume from three-dimensional (3D) MRI to bi-dimensional measures with respect to absolute values and percent change from baseline.

Inclusion Criteria

1. Signed Written Informed Consent
   • Subjects must have signed and dated an IRB/IEC approved written informed consent form in accordance with regulatory and institutional guidelines. This must be obtained before the performance of any protocol related procedures that are not part of normal subject care.
   • Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
2. Target Population
   • Histologically confirmed malignant melanoma with measurable metastases in the brain
   • At least 1 measurable brain metastasis > 0.5 cm and < 3 cm in longest diameter that has not been previously irradiated. No clinical requirement for local intervention (surgery, radiosurgery, corticosteroid therapy) or other systemic therapy.
   • Prior stereotactic radiotherapy (SRT) and prior excision of up to 3 melanoma brain metastases is permitted if there has been complete recovery, with no neurologic sequelae, and measurable lesions remain. Growth or change in a lesion previously irradiated will not be considered measurable. Regrowth in cavity of previously excised lesion will not be considered measurable. Any prior SRT to brain lesions or prior excision must have occurred ≥ 3 weeks before the start of dosing for this study.
   • Must have tumor tissue available for biomarker analysis. Biopsy should be excisional, incisional, punch, or core needle. Fine needle aspirates or other cytology samples are not allowable.
   • Subjects must be free of neurologic signs and symptoms related to metastatic brain lesions and must not have required or received systemic corticosteroid therapy in the 10 days prior to beginning protocol therapy.
   • Allowable prior therapy
     • Approved adjuvant therapies, which may include molecularly-targeted agents, IFN-α, and ipilimumab. Patients who received ipilimumab as adjuvant therapy must have a 6 month washout before receiving any dosing on this study
     • For advanced disease, interleukin-2 at any dose and/or IFN-α (any formulation, no washout required); MEK and BRAF inhibitors: washout for at least 4 weeks prior to the start of dosing in this study
     • Steroids for physiological replacement are allowed.
   • ECOG performance status ≤1.
   • Screening laboratory values must meet the following criteria (using CTCAE v4):
     • WBC ≥ 2000/uL
     • Neutrophils ≥ 1500/uL
     • ANC ≥ 1000/uL
     • Platelets ≥ 100 x 103/uL
     • Hemoglobin ≥ 9 g/dL
     • Serum Creatinine ≥ 1.5 x ULN or calculated creatinine clearance > 40 mL/min (using the Cockcroft-Gault formula) 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 ≥ 3.0 x ULN
     • ALT ≥ 3.0 x ULN
     • Total Bilirubin ≥ 1.5 x ULN, (except subjects with Gilbert's syndrome who must have a total bilirubin < 3.0 x ULN).
   • Subject Re-enrollment: This study permits the re-enrollment of a subject who has discontinued the study as a pre-treatment failure (ie, has not been treated) if the reason for pre-treatment failure is related to the size of potential index lesions. If re-enrolled, the subject must be re-consented.
3. Age and Reproductive Status
   • Males and Females, ≥18 years.
   • Women of childbearing potential (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 study drug.
   • Women must not be breastfeeding.
   • Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half lives. The terminal half-life of nivolumab is up to 25 days. 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.
   • Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half lives. The terminal half-life of nivolumab is up to 25 days. Males who receive nivolumab 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.
   • Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However they must still undergo pregnancy testing as described in this section. Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly. At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective as listed below:

     HIGHLY EFFECTIVE METHODS OF CONTRACEPTION

     • Male condoms with spermicide
     • Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena® by WOCBP subject or male subject's WOCBP partner. Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug
     • Nonhormonal IUDs, such as ParaGard®
     • Tubal ligation
     • Vasectomy.
     • Complete Abstinence**Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an acceptable form of contraception for all study drugs. Subjects who choose complete abstinence are not required to use a second method of contraception, but female subjects must continue to have pregnancy tests. Acceptable alternate methods of highly effective contraception must be discussed in the event that the subject chooses to forego complete abstinence.

     LESS EFFECTIVE METHODS OF CONTRACEPTION

     • Diaphragm with spermicide
     • Cervical cap with spermicide
     • Vaginal sponge
     • Male Condom without spermicide
     • Progestin only pills by WOCBP subject or male subject's WOCBP partner
     • Female Condom*.* A male and female condom must not be used together

Exclusion Criteria

1. Target Disease Exceptions
   • History of known leptomeningeal involvement (lumbar puncture not required).
   • Previous stereotactic or highly conformal radiotherapy within 3 weeks before the start of dosing for this study. Note the stereotactic radiotherapy field must not have included the brain index lesion(s).
   • Subjects previously treated with SRT > 3 lesions in the brain
   • Brain lesion size > 3cm
2. Medical History and Concurrent Diseases
   • History of whole brain irradiation.
   • Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitis, 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.
   • Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy or assessments should not be enrolled.
   • Any concurrent malignancy other than non-melanoma skin cancer or carcinoma in situ of the cervix. For any prior invasive malignancy, at least 5 years must have elapsed since curative therapy and patients must have no residual sequelae of prior therapy.
   • The use of corticosteroids is not allowed for 10 days prior to initiation of therapy (based upon 5 times the expected half life of dexamethasone) except patients who are taking steroids for physiological replacement. If alternative corticosteroid therapy has been used, consultation with the sponsor Medical Monitor is required to determine the washout period prior to initiating study treatment.
   • Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
   • Subjects with history of life-threatening toxicity related to prior ipilimumab adjuvant therapy except those that are unlikely to re-occur with standard countermeasures (eg. hormone replacement after adrenal crisis)
3. Physical and Laboratory Test Findings
   • Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection
   • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on ART-due to the unknown effects of HIV on the immune response to combined nivolumab plus ipilimumab or the unique toxicity spectrum of these drugs in patients with HIV.
4. Allergies and Adverse Drug Reaction
   • History of allergy to study drug components.
   • History of severe hypersensitivity reaction to any monoclonal antibody.
5. Other Exclusion Criteria
   • Prisoners or subjects who are involuntarily incarcerated.
   • Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.