Patient case: 72-year-old male with melanoma; genetic feature: TP53 loss of function

Clinical trial: Study to Evaluate the Safety, Tolerability and Pharmacokinetics of DS-3032b in Hematological Malignancies

Summary: This will be a Phase 1, open-label study of DS-3032b to assess its safety and tolerability and identify a Maximum Tolerated Dose (MTD)/tentative Recommended Phase II Dose (RP2D) in subjects with refractory or relapsed Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Myelogenous Leukemia (CML) in blast phase, or high risk MDS in Part 1-Dose Escalation and refractory or relapsed AML or high risk Myelodysplastic Syndrome (MDS) in Part 2-Dose Expansion.


Eligibility: Inclusion Criteria:
  -  Has one of the following diagnoses: Subjects must have refractory or relapsed AML or ALL, CML in blast phase, or high risk MDS (defined by Revised International Prognostic Scoring System [IPSS-R] score as High or Very High for inclusion in Part 1 of the study. Subjects must have refractory or relapsed AML or high-risk MDS (defined by IPSS-R score as High or Very High for inclusion in Part 2 of the study.
  -  Man or woman >= 18 years old.
  -  Has an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.
  -  Has adequate renal function, defined as: Creatinine clearance >=60 mL/min, as calculated using the modified Cockcroft Gault equation, ([{140 - age in years} × {actual weight in kg}] divided by [{72 × serum creatinine in mg/dL} multiply by 0.85 if female]), OR creatinine =< 1.5 X ULN
  -  Has adequate hepatic function, defined as:
  -  AST/ALT =<3 X ULN; -Bilirubin =<1.5 X ULN, unless resulting from hemolysis
  -  Has adequate blood clotting function, defined as: - International normalized ratio and activated partial thromboplastin time =<1.5 XULN
  -  Subject is able to provide written informed consent, comply with protocol visits and procedures, and take oral medication, and does not have any active infection or comorbidity that would interfere with therapy.
  -  Subject (male and female) of childbearing/ reproductive potential must agree to use double barrier contraceptive measures or avoid intercourse during the study and for 90 days after the last dose of study drug.
  -  Subject must be fully informed about their illness and the investigational nature of the study protocol (including foreseeable risks and possible side effects).
  -  Subject must sign and date an Institutional Review Board-approved informed consent form (including Health Insurance Portability and Accountability Act authorization, if applicable) before performance of any study-specific procedures or tests.
  -  Able and willing to provide bone marrow biopsies/aspirates as requested by the protocol.
  -  Is willing to undergo malignancy genotyping for TP53 gene mutation, insertion, or deletion at screening.
  -  Has a life expectancy of at least 3 months.
  Exclusion Criteria:
  -  Has a diagnosis of acute promyelocytic leukemia.
  -  Has a malignancy that contains a non synonymous mutation, insertion, or deletion in the TP53 gene determined previously or at screening.
  -  Presence of central nervous system involvement of leukemia or a history of primary central nervous system leukemia.
  -  Has a second concurrent primary malignancy that required active treatment within the previous 2 years, except for localized cancers that have apparently been cured, such as non-melanoma skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast.
  -  Any condition that would preclude adequate absorption of DS-3032b, including refractory nausea and vomiting, malabsorption, biliary shunt, significant bowel resection, and/or graft-versus-host disease (GVHD) affecting the gut.
  -  Has an uncontrolled infection requiring intravenous antibiotics, antivirals, or antifungals, known human immunodeficiency virus infection, or active hepatitis B or C infection.
  -  Has a concomitant medical condition that would in the opinion of the Investigator increase the risk of toxicity.
  -  Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE v4, Grade =<1 or baseline. Subjects with chronic Grade 2 toxicities may be eligible per discretion of the Investigator and Sponsor (eg, Grade 2 chemotherapy-induced neuropathy).
  -  Has received Hematopoietic Stem Cell Transplantation (HSCT) within 60 days of the first dose of DS-3032b, is on immunosuppressive therapy post-HSCT at the time of screening, or has clinically significant GVHD (use of topical steroids for ongoing skin GVHD will be permitted). Subjects must have a washout period of >=2 weeks or at least 4 half-lives from their last systemic immunosuppressive treatment for GVHD.
  -  Is receiving concomitant treatment with a strong inhibitor or inducer of CYP3A4/5.
  -  Received any therapies intended to treat malignancy within 21 days of first receipt of DS-3032b (except for hydroxyurea, which must be discontinued at least 48 hours prior to study treatment).
  -  Had major surgery within 4 weeks prior to study drug treatment.
  -  Participated in a therapeutic clinical study within 3 weeks before study drug treatment, or current participation in other therapeutic investigational procedures.
  -  Prolongation of corrected QT interval by Fridericia's method (QTcF) at rest, where the mean QTcF interval is >450 ms for males or >470 ms for females based on triplicate electrocardiograms (ECGs).
  -  Pregnant or breastfeeding.
  -  Substance abuse or medical, psychological, or social conditions that, in the opinion of the Investigator, may interfere with the subject's participation in the clinical study or evaluation of the clinical study results.
  -  Prior treatment with an MDM2 inhibitor.

Relevance to patient case: not relevant