Phase 1/2 Study of Oral MKC-1 Administered Twice Daily for 14 Consecutive Days Every 3 Weeks in Combination With Pemetrexed
1. Patients must satisfy this criteria based on the portion of the study for which they
are being considered for enrollment:
Dose Escalating Phase: Patients with advanced solid tumor malignancies for whom
single-agent pemetrexed therapy would not be contraindicated. Measurable disease not
Phase 2 portion: Current diagnosis of Stage IIIb (due to malignant pleural effusion
or supraclavicular lymph node involvement only) or Stage IV histologically and/or
cytologically proven non-small cell lung cancer according to staging system of the
American Joint Committee on Cancer.
(i) Patient has received maximally feasible surgical resection and/or radiotherapy
for initial disease.
(ii) Either disease progression following treatment with one prior chemotherapy
regimen used for the treatment of metastatic disease or disease progression
following adjuvant/neoadjuvant therapy within one year of last dose of chemotherapy
or (for those patients with disease progression following adjuvant/neoadjuvant
therapy >1 year of last dose of chemotherapy) disease progression following one
additional chemotherapy regimen for metastatic disease.
(iii) Radiographic or physical examination evidence of at least one site of
unidimensionally-measurable disease, using the RECIST criteria with disease assessed
within 28 days prior to treatment initiation.
2. Age ≥ 18 years.
3. ECOG performance status of 0 or 1.
4. All acute toxicity of any prior chemotherapy, surgery or radiotherapy must have
resolved to NCI CTCAE Grade ≤ 1, except for alopecia.
5. The following laboratory results, within 10 days of MKC-1 administration:
Hemoglobin ≥ 9 g/dL Absolute neutrophil count ≥ 1.5 x 109/L Platelet count ≥ 75 x
109/L Serum creatinine ≤ 1.5 x ULN (upper limit of normal) Creatinine clearance ≥ 45
mL/min AST ≤ 2.5 x ULN Serum albumin ≥ LLN (lower limit of normal) or 3.5 g/dL Total
bilirubin ≤ ULN
6. Signed informed consent.
1. Pre-existing hepatomegaly with disease measured as ≥ 2 cm below the costal margin,
secondary to malignancy.
2. Uncontrolled pleural effusions (defined as more than 2 pleuracenteses within 4 weeks
of the first dose of study drug)
3. Administration of cancer-specific therapy within the following periods prior to study
- less than 4 weeks prior: major surgery (this does not include placement of
venous access device or biopsy) or any investigational therapy;
- less than 3 weeks prior: radiation therapy or chemotherapy (except for oral
EGF-R receptor tyrosine kinase inhibitor(s);
- less than 2 weeks prior: oral EGF-R receptor tyrosine kinase inhibitor(s).
4. Pregnant or breast-feeding women. Female patients must be postmenopausal, surgically
sterile or they must agree to use a physical method of contraception. Female patient
with childbearing potential must have a negative pregnancy test within the 10 days
before the first MKC-1 administration. Male patients must be surgically sterile or
agree to use an acceptable method of contraception.
5. Known CNS or leptomeningeal metastases unless treated, clinically stable and not
6. Clinical evidence of bowel obstruction, active uncontrolled malabsorption syndromes
or a history of total gastrectomy.
7. Uncontrolled hypercalcemia (serum calcium-corrected > 12 mg/dL)
8. Serious cardiac condition (Class III/IV congestive heart failure according to New
York Heart Association classification); documented acute myocardial infarction within
the previous 6 months.
9. Any medical conditions that, in the investigator's opinion, would impose excessive
risk to the patient. Examples of such conditions include congestive heart failure of
Class III or IV of the NYHA classification, infection requiring parenteral or oral
anti-infective treatment, any altered mental status or any psychiatric condition that
would interfere with the understanding of the informed consent.
10. Patients with active secondary malignancies.
11. Treatment with antiretroviral therapy metabolized through CYP3A4 (including
indinavir, nelfinavir, ritonavir and saquinavir).