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Title A Phase 1/1b, Open-Label, Multicenter, Repeat-Dose, Dose-Selection Study of CPI-444 as Single Agent and in Combination with Atezolizumab in Patients with Selected Incurable Cancers

IRB CPI1Y16

CC 16-695

Hospital Main Campus

Phase Phase 1

Disease Bladder, Breast, Colorectal, Lung - NSCLC (Non-small cell lung cancer), Melanoma, Prostate, Renal

Drug Atezolizumab , CPI-444

Description

• Evaluate the safety and tolerability of multiple doses of CPI-444 administered on a daily schedule to subjects with selected incurable cancers as single agent and in combination with atezolizumab.
• Identify a recommended dose and schedule for further study of CPI-444 on the basis of safety, pharmacokinetic (PK), and pharmacodynamics data, to be used as single agent and in combination with atezolizumab.
• Evaluate the anti-tumor activity of CPI-444 in subjects with incurable cancer as single agent and in combination with atezolizumab.

• Characterize the PK of CPI-444 in subjects with incurable cancer as single agent and in combination with atezolizumab.
• Preliminary assessment of biologic markers that might predict CPI-444 anti-tumor activity as single agent and in combination with atezolizumab.
• Explore the effects of CPI-444 on lymphocyte subsets, cytokine production, immune function and tumor immunohistochemistry and gene expression as a single agent and in combination with atezolizumab.

Inclusion Criteria

1. Adult ≥ 18 years old. Ability to sign informed consent. However, if a subject is unable to read, understand and sign the Informed Consent Form, the subject's legally authorized representative (LAR) may provide consent on the subject's behalf if allowed by the Institutional Review Board or Ethics Committee.
2. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
3. A histologically or cytologically documented incurable cancer with a diagnosis for at least one of the following specific disease types: NSCLC, MEL, RCC, TNBC, and mCRPC, colorectal (MSI or mismatch repair deficient only), and urothelial bladder cancer. Indication-specific criteria are detailed in Section 4.4.
4. At least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST 1.1) with modification.
5. Previously treated brain or meningeal metastases must be without MRI evidence of progression compared to last brain imaging, and the patient must be off immunosuppressive doses of steroids (> 10 mg/day prednisone or equivalent) for at least 2 weeks prior to study drug administration.
6. Mandatory fresh tumor tissue samples will be collected in pairs (screening biopsy and "on-treatment" biopsy during Cycle 2). H&E staining to confirm tumor tissue is preferred but not required. Target lesions should not be biopsied. Only tissue from core needle, punch, or excisional biopsy sample collection will be accepted. Fine-needle aspiration, brushing, and lavage samples are not acceptable however in the event that no other biopsy method is available this should be discussed with the Sponsor. For all biopsy types, submitted blocks should have sufficient tissue to generate at least 15 unstained slides. If the pathology report specifies that the overall tumor content is low (e.g., "sparse" or "scant"), that tissue is not acceptable. Tissue from separate time points (such as time of initial diagnosis and time of metastatic diagnosis) or from the multiple metastatic tumors may also be collected for a given subject, on the basis of availability.

   Mandatory archival tumor tissue, either in paraffin blocks (preferred) or at least 15 unstained slides that were prepared within 3 months of enrollment. If available, the associated pathology report should be included along with prior PD-L1 test results. If more than one archival sample is available, the most recent sample is preferred.

7. Must have failed at least one curative or standard therapy option.
8. Subjects with NSCLC, must have progressed on or after platinum-based chemotherapy. Subjects with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, must have demonstrated disease progression on FDA-approved therapy for these aberrations. EGFR inhibitors include but not limited to gefitinib, erlotinib or cetuximab. ALK inhibitors include but not limited to crizotinib or ceritinib.
9. Subjects with melanoma, must have demonstrated disease progression following treatment with ipilimumab and/or nivolumab and/or pembrolizumab or other anti-CTLA-4, PD1 or PD-L1 antibodies approved by FDA for melanoma. If B Raf (BRAF) V600 mutation positive, must have progressed after a BRAF inhibitor such as but not limited to vemurafenib or dabrafenib.
10. At least one but not more than 5 prior systemic therapies for advanced/recurrent or progressing disease, and subject must not be eligible for potentially curative therapy. Adjuvant or neo-adjuvant systemic therapy will not be counted as part of the 5 prior systemic therapies.
11. Screening hematologic laboratory values as follows: ANC ≥ 1000/μL, platelets ≥ 75 x 103/μL, hemoglobin ≥ 9.0 g/dL.
12. Screening chemistry laboratory values as follows: AST/SGOT and ALT/SGPT ≤ 2.5 x institutional upper limit of normal (ULN) or ≤ 5 x ULN if hepatic metastasis, total bilirubin ≤ 2 x institutional ULN (except subjects with known history of Gilbert's syndrome, who must have total bilirubin < 3.0 mg/dL), serum creatinine ≤ 2 x institutional ULN or calculated or measured creatinine clearance ≥ 40 mL/min.
13. For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 56 days after the last dose of study treatment, or at least 5 months after the last dose of atezolizumab for subjects receiving combination treatment. A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.

Exclusion Criteria

1. History of severe hypersensitivity reaction to monoclonal antibodies for subjects in cohorts with combination therapy with atezolizumab.
2. Any active autoimmune disease or a documented history of serious autoimmune disease within the past 5 years requiring immunosuppressive therapy (e.g., steroids, cytotoxics, or TNF blockers), or history of a syndrome that required systemic steroids or immunosuppressive medications, except for subjects with controlled type I diabetes mellitus, endocrinopathies on stable doses of hormone replacement, vitiligo or resolved childhood asthma/atopy. Subjects with asthma who require only intermittent use of bronchodilators (such as albuterol) will not be excluded from this study.
3. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or clinical symptoms active pneumonitis. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
4. Monoclonal antibody therapy within 4 weeks or chemotherapy or radiotherapy within 2 weeks before study drug administration.
5. Unresolved acute toxicity of National Cancer Institute Common Terminology Criteria for AEs (NCI CTCAE) v4.03 Grade >1 (or baseline, whichever is greater) from prior anticancer therapy. Alopecia and other non-acute toxicities are acceptable.
6. An uncontrolled intercurrent illness including but not limited to ongoing or active infection symptomatic congestive heart failure (i.e., New York Heart Association [NYHA] Class 3 or 4), unstable angina pectoris, clinically significant and uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
7. Known history of human immunodeficiency virus (HIV) or active infection requiring therapy, or positive tests for hepatitis B surface antigen or hepatitis C ribonucleic acid (RNA).
8. Any live attenuated vaccination against infectious diseases (e.g., influenza, varicella) within 4 weeks (28 days) of initiation of study treatment.
9. A woman who is pregnant or breastfeeding.
10. The use of any investigational medication or device in the 30 days prior to initiation of study treatment (Cycle 1 Day 1) and throughout the study is prohibited.
11. The use of a RANKL inhibitor (denosumab) is not allowed for subjects randomized to the CPI-444 plus atezolizumab arm of the study. If a patient is taking a RANKL inhibitor, prior to enrollment, he/she must be willing and eligible to receive a bisphosphonate in the event that they are randomized to the combination cohort (denosumab could potentially alter the activity and the safety of atezolizumab). Subjects randomized to a single-agent cohort of the study may continue to take a RANKL inhibitor.