MC# 16-16 - A Phase I/Ib Study of MGCD516 in Patients With Advanced Solid Tumor Malignancies

  • Agent(s): MGCD516
  • Disease Type(s): Bladder, Breast, Cervical, Colorectal, Endometrial, Esophageal, Gastric, Head and Neck, Hepatocellular, Lung-NSCLC, Lung-SCLC, Melanoma, Mesothelioma, Neuroendocrine, Ovarian, Pancreatic, Prostate, Renal, Sarcoma, Solid Tumor, Squamous Cell, Thyroid
  • Phase(s): I
  • Drug Classification(s): Targeted Therapy, Small Molecule
  • Molecular Target(s): AXL, DDR2, KDR, KIT, MET, RET, TrkA, TrkB, TrkC, PDGFR

Mechanism of Action

MGCD516 is an orally-available, potent small molecule inhibitor of a closely related spectrum of receptor tyrosine kinases (RTKs) including MET, Axl family, VEGFR family, PDGFR family, KIT, FLT3, Trk family, RET, DDR2, and selected Eph family members.  Receptor tyrosine kinases (RTKs) are key regulators of signaling pathways leading to cell growth, survival, and migration.  Multiple MGCD516 RTK targets are genetically altered in a variety of cancer indications and act as oncogenic drivers promoting cancer development and progression.

Purpose

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

  • The effects of the MGCD516
  • How much MGCD516 is absorbed into the blood and how fast it is removed
Inclusion Criteria
  • Histologically confirmed diagnosis of an advanced solid tumor malignancy.
  • Unresectable or metastatic disease for which standard treatment is not available.
  • Age ≥18 years.
  • Life expectancy of at least 3 months.
  • Most recent prior therapy (e.g., chemotherapy, radiation therapy, or investigational agent) discontinued at minimum of 2 weeks before first dose date and resolution of toxicities from prior therapy to baseline or Grade 1.
  • Recovery from the adverse effects of prior therapy at the time of enrollment to ≤ Grade 1 (excluding alopecia).
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
  • Laboratory values within the screening period:
    • Absolute neutrophil count ³ 1,000/mm3 (³ 1.0 × 109/L)
    • Total bilirubin ≤1.5 x Upper Limit of Normal (ULN) (if associated with liver metastases or Gilbert’s disease, ≤3 × ULN
    • Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 × ULN (if ssociated with liver metastases, ≤5 × ULN).
    • Serum creatinine:
      • patient weight > 120 lbs, ≤3.0 × ULN or calculated creatinine clearance ≥ 30 cc/min
      • patient weight ≤ 120 lbs, ≤3.0 × ULN and calculated creatinine clearance ≥ 30 cc/min
  • Women of child-bearing potential (WOCBP) or men whose partner is a WOCBP agrees to use contraception while participating in this study, and for a period of 6 months following termination of study treatment.
  • Completed informed consent process, including signing IRB/EC-approved informed consent form.
  • Willing to comply with clinical trial instructions and requirements.

Inclusion criteria specific to enrollment into a Phase1b cohort:

  • For enrollment into a Phase 1b cohort, patients must have a selected diagnosis or test positive for a designated target tumor molecular marker in tumor tissue and/or ctDNA. Target molecular markers will be identified as the study progresses. Positive marker status for the purpose of eligibility must be established using a Sponsor pre-approved method and laboratory. A central laboratory is provided for eligibility screening for patients under consideration for enrollment in a designated Phase 1b cohort. If eligibility is established using a local laboratory, tumor specimens, should be available for retrospective confirmation of molecular markers. A representative paraffin embedded tumor block or a minimum of 12 unstained slides should be available for central laboratory evaluation. Specimens from recent biopsies are preferred, but archival biopsies are acceptable. Biopsies having significant risk should not be performed for the purpose of determining patient eligibility, including but not limited to biopsies of the lung/mediastinum or endoscopic procedures extending beyond the esophagus, stomach, or bowel. In the event that the minimum amount of tumor specimen is not available for central review and a new biopsy is not safe, enrollment must be approved by the Sponsor.

 

The Phase 1b segment will begin with the inclusion of the following cohorts of patients:

 

 Clear cell RCC refractory to angiogenesis inhibitors;

 mCRPC with bone metastases; and

 Patients with a solid tumor malignancy having a gene alteration of interest for MGCD516 (i.e., gene amplification, mutation or rearrangement in MET, AXL, RET, TRK, DDR2, KDR, PDGFRA, KIT or CBL).

 

Evaluable disease, either measurable or non-measurable, in accordance with RECIST Version 1.1.

Exclusion Criteria
  • Significant cardiac abnormalities within the past 6 months, such as myocardial infarction or congestive heart failure ≥Class 3; symptomatic or uncontrolled atrial fibrillation,
  • Prolonged QTc interval on electrocardiogram (ECG) >480 msec.
  • Patient requires ongoing treatment with concomitant medications known to cause QTc prolongation or known to be sensitive substrates or substrates with a narrow therapeutic index for P-gp and BCRP transporters.
  • Left ventricular ejection fraction (LVEF) less than 40%.
  • Patients with squamous cell lung carcinoma and who have either tumor lesions near a major blood vessel or large (> 2 cm) cavitating lesions or patients with a history of significant hemoptysis or hemorrhage within 4 weeks of first dose date.
  • Uncontrolled arterial hypertension (> 150 mm Hg systolic or > 100 mm Hg diastolic) on multiple observations despite standard of care treatment.
  • Symptomatic or uncontrolled brain metastases. Patients with symptoms suggestive of brain metastases must undergo screening CT or MRI scan of the brain. For patients with history of brain metastases, time elapsed since last cranial radiation must be at least 2 weeks and resolution of acute toxicities to Grade 1 or baseline.
  • Another active cancer (excluding basal cell carcinoma or cervical intraepithelial neoplasia (CIN / cervical in situ). Prior history of cancer is allowed, as long as there is no suspected active disease.
  • Pregnancy. WOCBP must have a negative serum or urine pregnancy test documented within the screening period prior start of study drug.
  • Breast-feeding or planning to breast feed during the study or within 30 days after study treatment.
  • Need for treatment with gastric pH modifying medications including proton pump inhibitors and/or H2 antagonist medications. Patients may switch to use of antacids.
  • Any uncontrolled inter-current illness, active or uncontrolled infection.
  • Any serious illness, medical condition, or other medical history, including laboratory results, which, in the Investigator’s opinion, would be likely to interfere with the patient’s participation in the study, or with the interpretation of the results.
  • Undergone major surgery within 4 weeks of first dose date.
  • Known human immunodeficiency virus (HIV) seropositivity or active Hepatitis B or C.
  • Any condition (e.g., known or suspected poor compliance, psychological instability, geographical location, etc.) that, in the judgment of the Investigator, may affect the patient’s ability to sign the informed consent and fully comply with all study procedures.
  • Any condition that will put the patient at undue risk or discomfort as a result of adherence to study procedures.

Exclusion criteria specific to enrollment into a Phase1b cohort:

  • Prior treatment with a therapy targeting the molecular marker of interest in the Phase 1b cohort being considered for enrollment. Specific prior therapies to be excluded based on the patient’s baseline characteristics will be decided following consultation between the Investigator and Sponsor. For example, a prior exposure to onartuzumab (MetMab) would not be considered an automatic exclusion due to differentiated inhibitory activity of MGCD516 for selected MET mutant variants and MET gene amplification.  In contrast, the activity of MGCD516 against RET gene rearrangements is not differentiated from other RET inhibitors including cabozantinib or sunitinib, so these prior therapies would be excluded for treatment of RET rearrangement positive lung cancers. Patients having multiple molecular markers of interest may be eligible if prior therapies targeted only one marker. Patients having RCC are expected to have previously received treatment with VEGF inhibitors and will not be excluded.
  • Clear cell RCC and mCRPC patients who received prior treatment with cabozantinib.

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT02219711?term=MGCD516&rank=1

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Re: MC# 16-16