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

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by Daiichi Sankyo Inc.
Sponsor:
Information provided by (Responsible Party):
Daiichi Sankyo Inc.
ClinicalTrials.gov Identifier:
NCT01877382
First received: June 11, 2013
Last updated: June 27, 2014
Last verified: June 2014
  Purpose

This will be a Phase 1, open-label study of DS-3032b to assess its safety and tolerability, identify an 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).


Condition Intervention Phase
Advanced Solid Tumor
Lymphoma
Drug: DS-3032
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 1 Multiple Ascending Dose Study of DS-3032b, an Oral MDM2 Inhibitor, in Subjects With Advanced Solid Tumors or Lymphomas

Resource links provided by NLM:


Further study details as provided by Daiichi Sankyo Inc.:

Primary Outcome Measures:
  • maximum tolerated dose [ Time Frame: 28 days ] [ Designated as safety issue: No ]
    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.

  • tumor response [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    To assess tumor response in subjects with melanoma using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 and in subjects with diffuse large B-cell lymphoma (DLBCL) using the revised International Working Group (IWG) criteria.


Secondary Outcome Measures:
  • plasma pharmacokinetics [ Time Frame: 28 days ] [ Designated as safety issue: No ]
    To determine the plasma pharmacokinetics (PK) of DS-3032a (the free form of DS-3032b).

  • effect on macrophage inhibitory cytokine-1 levels [ Time Frame: day 28 ] [ Designated as safety issue: No ]
    To determine the pharmacodynamic (PDy) effect of DS-3032b on macrophage inhibitory cytokine-1 (MIC-1) levels in serum.

  • determine relationship between tumor response and biomarker p53 [ Time Frame: day 8 ] [ Designated as safety issue: No ]
    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.

  • Determine PK profile of DS-3032a at the MTD/tentative RP2D [ Time Frame: day 28 ] [ Designated as safety issue: No ]
    To determine the PK profile of DS-3032a at the MTD/tentative RP2D.

  • Determine the PD effect of DS-3032b on MIC-1 levels in serum [ Time Frame: day 28 ] [ Designated as safety issue: No ]
    To determine the PD effect of DS-3032b on MIC-1 levels in serum.


Estimated Enrollment: 21
Study Start Date: July 2013
Estimated Study Completion Date: August 2015
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: DS-3032
DS-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.
Drug: DS-3032
DS-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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01877382

Contacts
Contact: Andrew Ruwe, PhD 513-579-9911 ext 2353 a.ruwe@medpace.com

Locations
United States, Michigan
Karmanos Cancer Institute Recruiting
Detroit, Michigan, United States, 48201
United States, New York
Memorial Sloan Kettering Cancer Center Recruiting
New York City, New York, United States, 10065
Contact: Collette Houston    646-735-8018      
United States, Tennessee
Tennessee Oncology Recruiting
Nashville, Tennessee, United States, 37203
United States, Texas
UT MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
Daiichi Sankyo Inc.
  More Information

No publications provided

Responsible Party: Daiichi Sankyo Inc.
ClinicalTrials.gov Identifier: NCT01877382     History of Changes
Other Study ID Numbers: DS3032-A-U101
Study First Received: June 11, 2013
Last Updated: June 27, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Lymphoma
Neoplasms
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases

ClinicalTrials.gov processed this record on August 20, 2014