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A Phase 1, Open-Label, Dose-Escalation Trial to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of MGCD0103 (MG-0103) in Combination With Docetaxel (Taxotere®) in Subjects With Advanced Solid Malignancies


Phase 1
18 Years
N/A
Not Enrolling
Both
Breast Cancer, Lung Cancer, Pulmonary Cancer, Non-Small-Cell Lung Carcinoma, Prostate Cancer, Prostatic Cancer, Gastric Cancer, Stomach Cancer

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Trial Information

A Phase 1, Open-Label, Dose-Escalation Trial to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of MGCD0103 (MG-0103) in Combination With Docetaxel (Taxotere®) in Subjects With Advanced Solid Malignancies


This Phase 1 study will evaluate escalating doses of orally administered MGCD0103 in
combination with two fixed doses (60 mg/m2 and 75 mg/m2) of IV docetaxel. In the US,
docetaxel is recommended at these or even higher doses (up to 100 mg/m2), both as a single
agent or in combination with other cytotoxic drugs (e.g., cisplatin, doxorubicin,
cyclophosphamide, and 5-fluorouracil), for the treatment of NSCLC, prostate cancer, gastric
adenocarcinoma, and head and neck cancer. In Japan, 60 mg/m2 IV docetaxel is the approved
dose for the treatment of breast cancer.

MGCD0103 belongs to the class of more selective, less globally cytotoxic agents being
investigated for treatment of cancers today, and may offer a lesser and/or non-overlapping
toxicity profile than the cytotoxic agents with which docetaxel is currently combined.
MGCD0103 doses ranging from 50 to 135 mg have been administered in combination with the
approved regimen of azacitidine (Vidaza®) (75 mg/m2/day for 5 days every 4 weeks) to
patients with high-risk MDS and AML. A 50 mg dose of MGCD0103 has been administered in
combination with the approved regimen of gemcitabine (1000 mg/m2 once weekly for 3
consecutive weeks of each 4-week cycle) to patients with advanced solid tumors; higher doses
of MGCD0103 will soon be evaluated in that trial.

Given the above, the proposed starting dose of 60 mg/m2 IV docetaxel and 50 mg MGCD0103 is
considered appropriately safe for initial investigation of this combination. Based on the
results observed in Part 1, the study may also evaluate 75 mg/m2 IV docetaxel and escalating
doses of orally administered MGCD0103 in Part 2 in order to determine whether this dosing
regimen is safe and would also warrant further investigation.


Inclusion Criteria:



Subjects must meet ALL inclusion criteria to be enrolled in the study

- Age ≥18 years.

- Diagnosis of malignant solid tumor (histologically or cytologically confirmed) where
treatment with docetaxel is considered standard of care, or advanced solid malignancy
that has failed to respond to standard therapy, or has progressed despite standard
therapy, or where there is no reasonable likelihood of achieving clinical benefit
with existing therapies.

- Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2.

- Adequate organ function, including: Hemoglobin (Hgb) ≥8.0g/dL; Absolute neutrophil
count (ANC) ≥1.5 x 10<9>/L (≥1500/mm<3>); Platelets ≥100 x 10<9>/L (≥100,000/mm<3>);
Total bilirubin ≤1.5 x ULN (upper limit of normal); AST (SGOT) and ALT (SGPT) ≤2.5 x
ULN; Alkaline phosphatase ≤5.0 x ULN; Serum creatinine ≤2.0 x ULN.

- Evidence of measurable disease (ie, at least one lesion that can accurately be
measured in at least one dimension as ≥20 mm with conventional techniques or ≥10 mm
with spiral CT scan). The requirement for measurable disease will not apply to
subjects with prostate cancer.

- A minimum of 4 weeks elapsed since any major surgery.

- At least 4 weeks elapsed since any prior anticancer therapy (standard or
investigational) and full recovery (NCI CTCAE grade 1) from the toxic effects of that
treatment. Antiandrogen therapy is permitted for subjects with prostate cancer.

- For women of childbearing potential, a negative serum pregnancy test within 10 days
of treatment, and use of physician-approved methods of birth control throughout the
study.

- Written, informed consent, willingness, and ability to comply with all study
procedures.

Exclusion Criteria:

Subjects meeting any of the following criteria will not be included in the study.

- Prior taxane and HDAC inhibitor combination therapy.

- Previous or concurrent malignancy except adequately treated basal cell or squamous
cell skin cancer; in situ carcinoma of the cervix, or other solid tumor treated
curatively, and without evidence of recurrence for at least 3 years prior to study
entry.

- Clinically significant cardiac disease including congestive heart failure (New York
Heart Association Class III or IV), including pre-existing ventricular arrhythmia or
conduction abnormality requiring medication, or cardiomyopathy.

- Active and uncontrolled clinically significant infection.

- History of melena, hematemesis, or hemoptysis within the last 3 months.

- Known central nervous system metastases controlled ≤3 months.

- Pregnant or lactating women. Women of child-bearing potential must have a negative
serum pregnancy test within 10 days of starting study drug on Day 1 Cycle 1.

- Known hypersensitivity to taxanes, HDAC inhibitors, and/or any components of MGCD0103
capsules or docetaxel formulation components (eg, polysorbate 80).

- Known HIV or known active Hepatitis B or C.

- Presence of serious illness, medical condition, or other medical history, including
abnormal laboratory parameters, which, in the opinion of the Investigator, would be
likely to interfere with a subject's participation in the study or with the
interpretation of the results.

- Any condition that will put the subject at undue risk or discomfort as a result of
adherence to study procedures (eg, requirement to take MGCD0103 with a low pH
beverage).

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), and safety profile of escalating doses of orally administered MGCD0103 in combination with two fixed doses (60 mg/m2 and 75 mg/m2) of IV docetaxel.

Outcome Time Frame:

15 months

Safety Issue:

Yes

Principal Investigator

Gregory Reid, MSc, MBA

Investigator Role:

Study Director

Investigator Affiliation:

MethylGene Inc.

Authority:

United States: Food and Drug Administration

Study ID:

103 PH US 2007 CL001

NCT ID:

NCT00511576

Start Date:

August 2007

Completion Date:

March 2009

Related Keywords:

  • Breast Cancer
  • Lung Cancer
  • Pulmonary Cancer
  • Non-Small-Cell Lung Carcinoma
  • Prostate Cancer
  • Prostatic Cancer
  • Gastric Cancer
  • Stomach Cancer
  • Advanced or Metastatic Breast Cancer
  • Breast Cancer
  • Advanced or Metastatic Non-Small-Cell Lung Cancer (NSCLC)
  • Hormone Refractory Prostate Cancer
  • Prostate Cancer
  • Gastric Cancer
  • Advanced Gastric Adenocarcinoma
  • HDAC Inhibitor
  • Taxotere
  • Docetaxel
  • Breast Neoplasms
  • Carcinoma
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms
  • Stomach Neoplasms
  • Prostatic Neoplasms

Name

Location

University of PennsylvaniaPhiladelphia, Pennsylvania  19104
Johns Hopkins, Sidney Kimmel Comprehensive Cancer CenterBaltimore, Maryland  21231