Study of HBI-8000 With Nivolumab in Melanoma, Renal Cell Carcinoma and Non-Small Cell Lung Cancer

A Phase 1b/2 Study to Assess the Safety and Efficacy of HBI-8000 in Combination With Nivolumab in Subjects With Advanced Solid Tumors Including Melanoma, Renal Cell Carcinoma (RCC), and Non-Small Cell Lung Cancer (NSCLC)

A Phase 1b/2 Study to Assess the Safety and Efficacy of HBI-8000 in Combination with Nivolumab in Patients with Advanced Solid Tumors Including Melanoma, Renal Cell Carcinoma (RCC), and Non-Small Cell Lung Cancer (NSCLC).

The primary objective of this study is:

-To evaluate the safety and tolerability of HBI-8000 when combined with a standard dose and regimen of nivolumab, and to evaluate frequency and severity of toxicities of this combination treatment

The secondary objectives of this study include:

• To explore the efficacy of study treatment as measured by Objective Response Rate (ORR), Disease Control Rate (DCR), Clinical Benefit Rate (CBR), Duration of Response (DoR), Progression-Free Survival (PFS) in all subjects treated at RP2D
• To obtain pharmacokinetics of twice weekly HBI-8000 when administered in combination with nivolumab administered once every two weeks (Phase 1b all sites)
• To obtain pharmacokinetics of twice weekly HBI-8000 when administered in combination with nivolumab administered per package insert dose and administration (Phase 2 selected sites)
• To characterize the effect of HBI-8000 on the electrocardiogram QT corrected (QTc) interval (Phase 1b only)

Exploratory:

• To investigate the kinetics and extent of histone acetylation in peripheral blood mononuclear cells (PBMC) at the RP2D of HBI-8000 (Phase 2 only)
• To explore potential biomarkers for disease response through sequential sampling of blood and/or tumor tissue in subjects consenting to correlative sub-studies at participating sites (Phase 2 only)

Dose Escalation (Phase 1b) will include up to 18 subjects, followed by Cohort Expansion (Phase 2) including up to 100 subjects (melanoma up to 60 subjects and NSCLC up to 40 subjects at MTD and/or RP2D.

A Phase 1b/2 Study to Assess the Safety and Efficacy of HBI-8000 in Combination with Nivolumab in Patients with Advanced Solid Tumors Including Melanoma, Renal Cell Carcinoma (RCC), and Non-Small Cell Lung Cancer (NSCLC).

The primary objective of this study is:

-To evaluate the safety and tolerability of HBI-8000 when combined with a standard dose and regimen of nivolumab, to determine Maximum Tolerated Dose (MTD) and/or Recommended Phase 2 Dose (RP2D) and to evaluate frequency and severity of toxicities of this combination treatment

The secondary objectives of this study include:

• To explore the efficacy of study treatment as measured by Objective Response Rate (ORR), Disease Control Rate (DCR), Clinical Benefit Rate (CBR), Duration of Response (DoR), Progression-Free Survival (PFS) in all subjects treated at RP2D
• To obtain pharmacokinetics of twice weekly HBI-8000 when administered in combination with nivolumab administered once every two weeks (Phase 1b all sites; Phase 2 selected sites)
• To characterize the effect of HBI-8000 on the electrocardiogram QT corrected (QTc) interval (Phase 1b only)

Exploratory:

-To investigate the kinetics and extent of histone acetylation in peripheral blood mononuclear cells (PBMC) at the RP2D of HBI-8000 (Phase 2 only)

Dose Escalation (Phase 1b) will include up to 18 subjects, followed by Cohort Expansion (Phase 2) including up to 100 subjects (melanoma up to 60 subjects and NSCLC up to 40 subjects) at MTD and/or RP2D.

HBI-8000 tablets will be administered at 20, 30, 40 mg/dose, orally twice a week until MTD or 40 mg in Phase 2, if MTD is not reached.

Nivolumab: 240 mg intravenous infusions every 2 weeks for Phase 1b and in accordance with the manufacturer package insert and institution's prescribing practice for Phase 2.

A treatment cycle consists of 28 days. Treatment continues until disease progression or unacceptable toxicity.

Inclusion Criteria

Subjects were entered in the study only if they met all of the following criteria:

1. Adults at least 18 years of age. 2. Eastern Cooperative Oncology Group (ECOG) performance status ≤1. 3.

1. Subjects with histopathologically or cytologically confirmed diagnosis of non uveal melanoma, RCC, or NSCLC, for whom the use of nivolumab was indicated. NSCLC subjects with EGFR or ALK genomic aberrations in tumor should have disease progression on FDA approved therapy for these aberrations prior to receiving nivolumab. (Phase 1b).
2. Subjects with histopathologically or cytologically confirmed diagnosis of non uveal melanoma or NSCLC for whom the use of nivolumab is indicated (Phase 2 expansion). With Protocol Amendment 5, subjects with NSCLC were not eligible for enrollment.

c, Non uveal melanoma and NSCLC subjects whose disease progressed after achieving stable disease (SD) for at least 3 months, with partial response (PR) or complete response (CR) as the best response that was documented by imaging studies on previous treatment with a PD L1 inhibitor with proven efficacy (Phase 2 expansion). With Protocol Amendment 5, subjects with NSCLC were not eligible for enrollment.

4. Subject had at least one measurable target lesion as defined by Response Evaluation Criteria in Solid Tumors v1.1 (RECIST 1.1). Melanoma subjects participating in the optional correlative substudy had tumor tissue available from a metastatic or unresectable site for PD L1 and correlative biomarker analysis.

5. All prior systemic therapy (chemotherapy, mutation targeting therapy, immune checkpoint therapy), or surgical or radiation treatment was completed at least 4 weeks before study drug* administration (2 weeks for palliative radiotherapy, 1 week for minor surgery), pending full recovery from therapy.

6. The following laboratory results within 7 days prior to study drug* administration: Adequate hematopoietic, electrolyte, hepatic, and renal laboratory findings as defined below: white blood cells (WBC) ≥3000/μL, neutrophils ≥1500/μL, platelets ≥100x103/μL, hemoglobin ≥9.0 g/dL independent of transfusion, creatinine ≤1.5 mg/dL, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × upper limit of normal (ULN), alkaline phosphatase ≤2.5 x ULN (unless bone metastases present), bilirubin ≤1.5 × ULN (unless known Gilbert's disease, where value must be ≤3 × ULN), and serum albumin ≥3.0 g/dL.

7. Life expectancy ≥12 weeks. 8. A negative serum pregnancy test at baseline for women of childbearing potential.

9. Were willing to abstain from heterosexual activity or practice physical barrier contraception prior to time of study entry to at least 5 months after the last day of treatment.

10. Had the ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

Subjects who fulfilled any of the following criteria at screening were not eligible for admission into the study:

1. History of Grade 3 or above hypersensitivity reactions to other monoclonal antibodies.
2. Subjects with a history of a cardiovascular illness including: congestive heart failure (New York Heart Association Grade III or IV); unstable angina or myocardial infarction within the previous 6 months; or symptomatic cardiac arrhythmia despite medical management. In addition, for Phase 1b only: QTc (Fridericia's correction) (QTcF) >450 ms in male, and >470 ms in female, congenital long QT syndrome.
3. Uncontrolled hypertension, systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg.
4. Subjects with active brain metastasis; previously treated brain metastasis was allowed if it had been stable for 4 weeks or more and had not required steroids.
5. Presence of leptomeningeal disease.
6. History of hemorrhagic diarrhea, inflammatory bowel disease, active uncontrolled peptic ulcer disease, recurrent pleural effusion requiring repetitive palliative thoracentesis within 3 months prior to study entry (except for subjects with a pleurex port), or immune mediated toxicity leading to treatment discontinuation.
7. Active, known, or suspected serious autoimmune disease, except for type I diabetes mellitus, hypothyroidism only requiring hormone replacement, and skin disorders (such as vitiligo, psoriasis, or alopecia).
8. Active uncontrolled bacterial, viral, or fungal infection requiring systemic therapy.
9. Known history of testing positive for human immunodeficiency virus (HIV), known acquired immunodeficiency syndrome (AIDS).
10. Active hepatitis B (serum hepatitis B surface antigen [HBsAg] positive) or hepatitis C (hepatitis C virus [HCV] antibody test or serum HCV RNA positive) indicating acute or chronic infection.
11. 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 were permitted.
12. Use of other investigational agents (drugs not marketed for any indication) within 28 days or at least 5 half lives (whichever is shorter) before study drug administration.
13. Pregnant or breast feeding women.
14. Second malignancy unless in remission for 2 years, except for non melanomatous skin cancer, carcinoma in situ of the cervix treated with curative intent, or curatively treated prostate cancer with prostate specific antigen (PSA) <0.1 ng/mL.
15. Underlying medical conditions that, in the Investigator's opinion, made the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events.
16. Unwilling or unable to comply with procedures required in this protocol.