MC# 16-14 - A Phase I/Ib, 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

  • Agent(s): CPI-444
  • Disease Type(s): Prostate
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): A2A

Mechanism of Action

CPI-444 selectively and reversibly binds adenosine-2A receptors (A2AR) on T-lymphocytes and other cells of the immune system.  Adenosine is one of multiple inhibitory checkpoint signals (including PD1/PDL1 and CTLA4) that normally prevent reaction, or overreaction, to self-antigens, and CPI-444 is proposed to be a next-generation immunotherapeutic agent.

Purpose

In this study, the sponsor, Corvus Pharmaceuticals, and investigators want to learn:

  • how safe CPI-444 (study drug 1) is alone and in combination with atezolizumab (study drug 2)
  • how much of study drug 1 can be given on its own, and in combination with study drug 2, with an acceptable level of side effects
  • about the effects (good and bad) of the study drugs on a subject’s disease, including changes in subject’s tumor
  • how much of the study drug is absorbed into the blood and how fast it is removed
  • if research tests can predict who will benefit from study drug 1 alone or in combination with study drug 2
Inclusion Criteria
  • Adult ≥ 18 years old.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
  • A histologically or cytologically documented incurable cancer with a diagnosis for at leastone 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.
  • At least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST)v1.1.
  • Previously treated brain or meningeal metastases must be without CT/MRI evidence ofprogression compared to last brain imaging, and the patient must be off immunosuppressivedoses of steroids (> 10 mg/day prednisone or equivalent) for at least 2 weeks prior to studydrug administration.
  • A. Mandatory fresh tumor tissue samples will be collected in pairs (screening biopsy and “on-treatment” biopsy during Cycle 2) for Steps 1 and 2. H&E staining to confirm tumor tissue is preferred but not required. Target lesions must not be biopsied. Adequate medical justification must be provided to the Medical Monitor for cases in which the fresh biopsies cannot be obtained. A recent biopsy ontained within 3 months of screening may be submitted in place of the screening biopsy, provided that no anti-cancer treatment was received since the biopsy, after discussion with the Medical Monitor. Fresh paired biopsies are not required for subjects enrolled into Steps 3 and 4 (archival tissue is required).                                                                                                                                                                                                                                                                          B. Mandatory archival tumor tissue for Steps 1, 2, 3, and 4, 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. 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. If archival tissue is not available, a fresh tumor tissue biopsy may be submitted in place of archival tissue after discussion with the Medical Monitor.                                                                                                                                                                                                                                                                                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 Medical Monitor. 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.
  • Must have failed at least one curative or standard therapy option.
  • Subjects with NSCLC, must have progressed on or after treatment with a platinum-basedchemotherapy or a PD(L)1 antibody. Subjects with epidermal growth factor receptor (EGFR)or anaplastic lymphoma kinase (ALK) genomic tumor aberrations, must have demonstrateddisease progression on FDA-approved therapy for these aberrations. EGFR inhibitorsinclude but not limited to gefitinib, erlotinib or cetuximab. ALK inhibitors include but notlimited to crizotinib or ceritinib.
  • Subjects with melanoma, must have demonstrated disease progression following treatment with ipilimumab and/or nivolumab and/or pembrolizumab and/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.
  • At least one but not more than 5 prior systemic therapies for advanced/recurrent or metastatic disease, and subject must not be eligible for potentially curative therapy. Adjuvant or neo-adjuvant systemic therapy will be counted as part of the 5 prior systemic therapies if the subject has relapsed disease within 6 months of completing adjuvant or neo-adjuvant therapy. For RCC subjects, number of prior regimens differs from above.
  • Screening hematologic laboratory values as follows: ANC ≥ 1000/μL, platelets ≥ 75 x 103/μL, hemoglobin ≥ 9.0 g/dL.
  • Screening chemistry laboratory values as follows: AST/SGOT and ALT/SGPT ≤ 2.5 × institutional upper limit of normal (ULN) or ≤ 5 × ULN if hepatic metastasis, total bilirubin ≤ 2 × institutional ULN (except subjects with known history of Gilbert’s syndrome, who must have total bilirubin < 3.0 mg/dL), serum creatinine ≤ 2 × institutional ULN or calculated or measured creatinine clearance ≥ 40 mL/min. LDH < 3 × institutional ULN.
  • 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 CPI-444, 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.
  • No single tumor site ≥ 16 cm.
  • Life expectancy ≥ 12 weeks.
  • 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.
  • Willing and able to comply with all study requirements and procedures.
Exclusion Criteria
  • History of severe hypersensitivity reaction to monoclonal antibodies for subjects in cohorts with combination therapy with atezolizumab.
  • 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.
  • History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or clinical symptoms of active pneumonitis. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
  • Monoclonal antibody therapy within 4 weeks or chemotherapy or radiotherapy within 2 weeks before study drug(s) administration.
  • Unresolved acute toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 Grade >1 (or baseline, whichever is greater) from prior anticancer therapy. Alopecia and other nonacute toxicities are acceptable.
  • An uncontrolled intercurrent illness including but not limited to ongoing or active infection (including fever within 48 hours of screening), 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.
  • 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).
  • Any live attenuated vaccination against infectious diseases (e.g., influenza, varicella) within 4 weeks (28 days) of initiation of study treatment.
  • A woman who is pregnant or breastfeeding
  • The use of any investigational medication or device in the 30 days prior to initiation of study treatment and throughout the study is prohibited
  • The use of a RANKL inhibitor (denosumab) is not allowed for subjects allocated 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 allocated to the combination cohort (denosumab could potentially alter the activity and the safety of atezolizumab). Subjects allocated to a single-agent cohort of the study may continue to take a RANKL inhibitor.
  • History of invasive prior malignancy that required systemic therapy within the last 5 years

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT02655822

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Re: MC# 16-14