Clinical Trials /

A Phase 1 Multiple Ascending Dose Study of DS-3032b, an Oral Murine Double Minute 2 (MDM2) Inhibitor, in Subjects With Advanced Solid Tumors or Lymphomas

NCT01877382

Description:

This will be a Phase 1, open-label study of DS-3032b to assess its safety and tolerability, identify a maximum tolerated dose (MTD)/tentative recommended phase 2 dose (RP2D), and assess its pharmacokinetic (PK)/ pharmacodynamic (PD) properties in subjects with advanced solid tumors or lymphomas. Approximately 5 US sites are planned for Part 1 (Dose Escalation). Approximately 10 US sites are planned for Part 2 (Dose Expansion).

Related Conditions:
  • Lymphoma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Phase 1 Multiple Ascending Dose Study of DS-3032b, an Oral Murine Double Minute 2 (MDM2) Inhibitor, in Subjects With Advanced Solid Tumors or Lymphomas
  • Official Title: A Phase 1 Multiple Ascending Dose Study of DS-3032b, an Oral MDM2 Inhibitor, in Subjects With Advanced Solid Tumors or Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: DS3032-A-U101
  • NCT ID: NCT01877382

Conditions

  • Advanced Solid Tumor
  • Lymphoma

Interventions

DrugSynonymsArms
DS-3032DS-3032

Purpose

This will be a Phase 1, open-label study of DS-3032b to assess its safety and tolerability, identify a maximum tolerated dose (MTD)/tentative recommended phase 2 dose (RP2D), and assess its pharmacokinetic (PK)/ pharmacodynamic (PD) properties in subjects with advanced solid tumors or lymphomas. Approximately 5 US sites are planned for Part 1 (Dose Escalation). Approximately 10 US sites are planned for Part 2 (Dose Expansion).

Trial Arms

NameTypeDescriptionInterventions
DS-3032ExperimentalDS-3032b will be administered as an oral capsule. It will be supplied in 5 mg, 20 mg, 80 mg, and 200 mg capsules individually packaged in desiccant-embedded aluminum blisters.
  • DS-3032

Eligibility Criteria

        Inclusion Criteria:

          -  Has a histologically or cytologically documented advanced solid tumor or lymphoma that
             has relapsed from or is refractory to standard treatment, or for which no standard
             treatment is available. Subjects with melanoma who are ineligible to receive or have
             declined ipilimumab treatment, or who are refractory or intolerant to ipilimumab may
             enroll.

          -  Man or woman >= 18 years old.

          -  Has an Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

          -  Has adequate bone marrow function, defined as:

        Platelet count >= 100 x 109/L Hemoglobin >= 9.0 g/dL Absolute neutrophil count >= 1.5 x
        109/L.

        - 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 levels =< 3 x ULN (if liver metastases
        are present, =< 5 x ULN) Bilirubin =< 1.5 x ULN.

        - Has adequate blood clotting function, defined as: International normalized ratio (INR)
        and activated partial thromboplastin time (aPTT) =< 1.5 x ULN.

          -  Subject should be able to provide written informed consent, comply with protocol
             visits and procedures, be able to take oral medication, and 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) and must
             sign and date an IRB [Institutional Review Board]-approved Informed consent Form [ICF]
             (including Health Insurance Portability and Accountability Act authorization, if
             applicable) before performance of any study specific procedures or tests.

          -  Is willing to provide and there is confirmed availability of pre-existing diagnostic
             or resected tumor samples, such as paraffin-embedded sections. Providing fresh tumor
             biopsy is optional for subjects in Dose Escalation cohorts.

          -  Is willing to undergo tumor genotyping for TP53 mutation, insertion, or deletion at
             screening. Confirmation of TP53 nonmutant status is encouraged, but not required prior
             to DS-3032b dosing.

          -  Is willing to provide additional archived samples for comprehensive genomic and/or
             proteomic analyses if the subject has a partial response/complete response to DS-3032b
             treatment.

        Exclusion Criteria:

          -  Has a tumor that contains a nonsynonymous mutation, insertion, or deletion in the TP53
             gene determined previously or at screening.

          -  Has a history of primary central nervous system malignancy.

          -  Has gastrointestinal conditions that could affect the absorption of DS-3032b in the
             opinion of the Investigator.

          -  Has an uncontrolled infection requiring intravenous antibiotics, antivirals, or
             antifungals, known human immunodeficiency virus infection, or active hepatitis B or C
             infection.

          -  Has received an allogeneic bone marrow or allogeneic stem cell transplant.

          -  Has a concomitant medical condition that would increase the risk of toxicity, in the
             opinion of the Investigator or Sponsor.

          -  Has clinically active brain metastases, defined as untreated and symptomatic, or
             requiring therapy with steroids or anticonvulsants to control associated symptoms.
             Subjects with treated brain metastases that are no longer symptomatic and who require
             no treatment with steroids may be included in the study if they have recovered from
             the acute toxic effect of radiotherapy. A minimum of 4 weeks must have elapsed between
             the end of whole brain radiotherapy and study enrollment (2 weeks for stereotactic
             radiotherapy).

          -  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 the discretion of the
             Investigator and Sponsor (eg, grade 2 chemotherapy-induced neuropathy).

          -  Had an autologous transplant within 3 months of starting study drug treatment.

          -  Is receiving concomitant treatment with a strong inhibitor or inducer of CYP3A4/5.

          -  Had systemic treatment with anticancer therapy, antibody-based therapy, retinoid
             therapy, or hormonal therapy within 3 weeks before study drug treatment; or treatment
             with nitrosoureas or mitomycin C within 6 weeks before study drug treatment; or
             treatment with small-molecule targeted agents within 2 weeks before study drug
             treatment. Previous and concurrent use of hormone replacement therapy, the use of
             gonadotropin releasing hormone modulators for prostate cancer, and the use of
             somatostatin analogs for neuroendocrine tumors are permitted if such therapy has not
             been changed within 8 weeks before study drug treatment.

          -  Had therapeutic radiation therapy or major surgery within 4 weeks before study drug
             treatment or palliative radiation therapy within 2 weeks before 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 milliseconds (ms) for males and > 470 ms for females based
             on triplicate ECG.

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:maximum tolerated dose
Time Frame:28 days
Safety Issue:
Description:To determine the maximum tolerated dose (MTD) or tentative recommended Phase 2 dose (RP2D) of DS-3032b in subjects with advanced solid tumors or lymphomas.

Secondary Outcome Measures

Measure:plasma pharmacokinetics
Time Frame:28 days
Safety Issue:
Description:To determine the plasma pharmacokinetics (PK) of DS-3032a (the free form of DS-3032b).
Measure:effect on macrophage inhibitory cytokine-1 levels
Time Frame:day 28
Safety Issue:
Description:To determine the pharmacodynamic (PDy) effect of DS-3032b on macrophage inhibitory cytokine-1 (MIC-1) levels in serum.
Measure:determine relationship between tumor response and biomarker p53
Time Frame:day 8
Safety Issue:
Description:To evaluate the relationship between tumor response to DS-3032b and predictive biomarkers (e.g. p53, p21, p14, p16, MDM2, MDM4) studied in archived tumor samples and pre treatment tumor biopsies.
Measure:Determine PK profile of DS-3032a at the MTD/tentative RP2D
Time Frame:day 28
Safety Issue:
Description:To determine the PK profile of DS-3032a at the MTD/tentative RP2D.
Measure:Determine the PD effect of DS-3032b on MIC-1 levels in serum
Time Frame:day 28
Safety Issue:
Description:To determine the PD effect of DS-3032b on MIC-1 levels in serum.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Daiichi Sankyo, Inc.

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