MC# 18-18 - A Phase II, Randomized, Open-label Study to Evaluate the Efficacy, Safety, Tolerability, and Pharmacokinetics of M6620 in Combination with Avelumab and Carboplatin in Comparison to Standard of Care Therapy in Participants with PARPi-resistant Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

  • Agent(s): M6620, Avelumab, Carboplatin
  • Disease Type(s): Ovarian
  • Phase(s): II
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): ATR

Mechanism of Action

M6620 is an inhibitor of ATR kinase.  (ATR kinase = ataxia telangiectasia mutated and RAD3 related kinase). ATR kinase is a component of DNA damage repair pathways. In preclinical studies M6620 sensitizes tumor cells to the effects of DNA damaging chemotherapy agents and to the effects of radiation.

Purpose

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

  • How much M6620 can be given with an acceptable level of side effects when used in combination with Avelumab and Carboplatin
  • The effects of M6620 when given in combination with Avelumab and Carboplatin compared to the standard-of-care treatment
  • How fast M6620 is removed from the body
  • How the body’s immune system reacts to M6620
Inclusion Criteria
  • Are ≥ 18 years of age, at the time of signing the informed consent.
  • Female participants with recurrent epithelial ovarian cancer who have disease progression following maintenance treatment with a PARPi as defined below:
    • Participant must have histologically diagnosed epithelial ovarian, primary peritoneal, or fallopian tube cancer, with nonmucinous histology
    • Participants must have completed at least 2 previous courses of platinum-containing therapy (eg, carboplatin or cisplatin) and had documented response (complete response [CR] or partial response [PR]) to the last platinum-based treatment prior to treatment with a PARPi
    • Participant has received the last dose of platinum-containing treatment at least 6 months prior to study enrollment
    • Participant has documented disease progression (radiological) after at least 6 months of maintenance treatment with PARPi following a response to platinum-based chemotherapy.
    • Confirmed BRCA 1/2 mutation status or agree to its testing on samples collected in the study.
  • Available formalin-fixed, paraffin-embedded (FFPE) tumor biopsies.
    • Part A: Participant should be willing to undergo 2 paired on-treatment biopsies on Day 2 of Cycle 1 or Cycle 2, before and after M6620 administration, if assessed as feasible at low risk by the interventional radiologist.
    • Part B: Histological tissue specimen (tissue block or 8 to 10 unstained slides) must be available. An archival tumor biopsy is acceptable if obtained after the last progression on PARPi treatment and is less than 6 months old. Otherwise, participants must be willing to undergo mandatory biopsy during the Screening Period to obtain sufficient tissue for histological assessment. Participants need to have an attempted biopsy. However, participants who have measurable disease documented by a radiologist as not feasible or safe to be biopsied are eligible to enter the study.
  • Measurable disease according to RECIST v1.1.
  • Greater than 28 days from and recovered from prior radiation therapy or surgery.
  • Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1 at study entry at Screening.
  • Adequate hematological function as defined below:
    • Hemoglobin > 9 g/dL.
    • Platelet count ≥ 100 × 109/L
    • Lymphocyte count ≥ 0.5 × 109/L
    • Absolute neutrophil count ≥ 1.5 × 109/L
    • White blood cell count ≥ 3.0 × 109/L
  • Adequate hepatic function as defined below:
    • A total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range. Participants with documented Gilbert disease are allowed if total bilirubin > 1.5, but less   than 3 × ULN
    • Aspartate aminotransferase (AST) levels ≤ 3.0 × ULN (≤ 5 × ULN in case of liver metastases)
    • Alanine aminotransferase (ALT) levels ≤ 3.0 × ULN (≤ 5 × ULN in case of liver metastases)
    • Serum albumin concentrations ≥ 35 g/L (3.5 g/dL).
  • Adequate renal function defined by an estimated creatinine clearance ≥ 50 mL/min according to the Cockcroft-Gault formula.
  • A female participant is eligible if she is not pregnant (ie, after a confirmed menstrual period and a negative serum pregnancy test), not breastfeeding, and at least 1 of the following conditions applies to her:
    • Is not a woman of childbearing potential (WOCBP), as defined in the study protocol OR Is a WOCBP who agrees to use a highly effective contraceptive method (ie, has a failure rate of less than 1% per year), as listed in the study protocol, from 1 menstrual cycle before the cycle preceding the start of the first dose of study intervention (as appropriate), during the study intervention period (Parts A and B), and for at least 60 days after the last dose of study intervention.
  • Can give signed informed consent, as indicated in the study protocol, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and this protocol.
Exclusion Criteria
  • All participants with brain metastases, except those meeting the following criteria:
    • Brain metastases that have been treated locally and are clinically stable for at least 4 weeks prior to randomization
    • Participants must not be taking steroids.
    • No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)
  • Prior organ transplantation, including allogeneic stem cell transplantation.
  • Previous malignant disease (other than the indication for this study) within the last 5 years (except adequately treated nonmelanoma skin cancers or carcinoma in situ of any of the following tissues: skin, bladder, cervix, colon/rectum, or breast) unless a complete remission without further recurrence was achieved at least 2 years prior to study entry and the participant was deemed to have been cured with no additional therapy required or anticipated to be required.
  • Active infection requiring systemic therapy:
    • Known history of human immunodeficiency virus or known acquired immunodeficiency syndrome
    • Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at Screening (positive HBV surface antigen or HCV ribonucleic acids [RNAs] if anti-HCV antibody screening test positive).
  • Active or history of autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with type I diabetes mellitus, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
  • Known severe hypersensitivity reactions to fully human monoclonal antibodies (Grade ≥ 3 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE]) or to any components of the DDRi- or DNA-damaging anticancer therapy to be tested as well as known hypersensitivity to any of excipients.
  • Uncontrolled asthma
  • Persisting toxicity related to prior therapy (NCI-CTCAE Grade > 1); however, alopecia Grade ≤ 2, or other Grade ≤ 2 AEs not constituting a safety risk based on Investigator’s judgment are acceptable.
  • Uncontrolled intercurrent illness including, but not limited to:
    • Hypertension uncontrolled by standard therapies (not stabilized to 150/90 mmHg or lower)
    • Uncontrolled active infection
    • Uncontrolled diabetes (eg, glycosylated hemoglobin ≥ 8%).
  • Clinically significant (ie, active) cardiovascular disease: cerebral vascular accident or stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class ≥ II), or serious cardiac arrhythmia requiring medication.
  • Known history of inflammatory colitis, inflammatory bowel disease, pneumonitis/interstitial lung disease, or pulmonary fibrosis.
  • Other severe acute or chronic medical conditions; psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study intervention administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the participant inappropriate for entry into this study.
  • Any participant with intercurrent bone fracture that may be at risk of delayed healing due to protocol therapy.
  • History of tumor bleeding.
  • History of congenital or active immunodeficiency, except for acquired treatment-related hypogammaglobulinemia requiring periodic intravenous (iv) immunoglobulin infusion.
  • Participants who have been diagnosed with Li-Fraumeni syndrome or ataxia telangiectasia.
  • Treatment with a nonpermitted drug/intervention as listed below:
    • Concurrent anticancer treatment (eg, cytoreductive therapy, radiotherapy, immune therapy, cytokine therapy, monoclonal antibody, or targeted small molecule therapy) or any study intervention within 4 weeks prior to start of study intervention, or not recovered from AEs related to such therapies, with the following exceptions:
      • Hormonal therapies acting on the hypothalamic-pituitary-gonadal axis are permitted (ie, luteinizing hormone-releasing hormone agonist/antagonists). No other hormonal anticancer therapy is permitted.
      • Investigational DNA-damaging treatment or chemotherapy as defined for the specific cohort in this study.
  • For prior chemotherapy with platinum-containing agents:
    • History of prior dose reductions or dose interruptions while receiving cisplatin or carboplatin due to toxicity from the platinum or intolerance to either agent, unless discussed with and approved by the Sponsor Medical Monitor.
  • Major surgery (as deemed by Investigator) for any reason, except diagnostic biopsy, within 4 weeks prior to start of study intervention, or not fully recovered from surgery within 4 weeks prior to start of study intervention.
  • Prior treatment with a PD-1/PD-L1 targeting agent.
  • Current use of the following medications at the time of enrollment:
    • Immunotherapy or immunosuppressive drugs (eg, chemotherapy or systemic corticosteroids) EXCEPT for the following:
      • Intranasal, inhaled, topical steroids, or local steroid injection (eg, intra-articular injection)
      • Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent
      • Steroids as premedication for hypersensitivity reactions (eg, computed tomography [CT] scan premedication).
    • Growth factors (eg, granulocyte colony stimulating factor or granulocyte macrophage colony stimulating factor) EXCEPT where indicated for treatment of study intervention-related myelosuppression and for prophylaxis of repeat myelosuppression after initial occurrence.
    • Herbal remedies with immunostimulating properties (eg, mistletoe extract) or known to potentially interfere with major organ function (eg, hypericin).
    • Other DNA damage repair inhibitors (except PARPi) (eg, inhibitors of ATR, ataxia telangiectasia mutated [ATM] kinase, DNA-dependent protein kinase [DNA-PK], or Wee kinases).
  • Administration of a live vaccine within 30 days prior to study enrollment.
  • Participants receiving treatment with ototoxic or nephrotoxic medications that cannot be discontinued at least 7 days before first dose of carboplatin as part of the study intervention and for the duration of the study.
  • Participants receiving treatment with medications that are known to be strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) that cannot be discontinued for at least 1 week before the start of treatment and for the duration of the study.
  • Known alcohol or drug abuse as deemed by the Investigator.
  • Any psychiatric condition that would prohibit the understanding or rendering of informed consent or that would limit compliance with study requirements.
  • Legal incapacity or limited legal capacity.

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03704467?term=M6620&phase=1&rank=5

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Re: MC# 18-18