Dinaciclib in Treating Patients With Advanced Melanoma

PRIMARY OBJECTIVES:

I. The primary objective of the phase 1 part of this study is to determine the recommended
phase 2 dose of SCH727965 administered as a 4-hour infusion every other week in patients
with advanced malignant melanoma.

II. The primary objective of the phase 2 part of this study is to determine the 1-year
overall survival of patients with malignant melanoma treated with SCH727965 at the dose and
schedule derived in the phase 1 part of the study.

SECONDARY OBJECTIVES:

I. To characterize the safety profile and toxicities of SCH727965 administered as a 4-hour
infusion every other week.

II. To determine the pharmacokinetics of SCH727965 administered as a 4-hour infusion every
other week.

III. To determine the proportion of patients with malignant melanoma who are alive without
progression of disease 6 months after beginning treatment with SCH727965 at the dose and
schedule derived in the phase 1 part of the study.

IV. To determine the objective response rate to SCH727965 of patients with malignant
melanoma enrolled to part 2 of the study.

V. To document cdk2, combined cdk2/1 and cdk9 inhibition in surrogate tissues and tumor.

VI. To correlate the degree of change of pharmacodynamic parameters in post-treatment
compared to pre-treatment samples with clinical outcome.

VII. To correlate the degree of change of parameters defining cdk2, cdk2/1 and cdk9
inhibition with pharmacokinetic parameters.

VIII. To correlate pre-treatment cdk2 levels with the degree of change of parameters
measuring cdk2 inhibition.

IX. To correlate pre-treatment cdk2 levels with clinical outcome. X. To correlate tumor p53
status with clinical outcome.

OUTLINE:

Patients receive dinaciclib intravenously (IV) over 4 hours on day 1. Courses repeat every
14 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months .

Inclusion Criteria:

- Patients must have normal organ and marrow function as defined below:

Absolute Neutrophil Count >= 1.5 x 10^9/L; Platelets >= 100 x 10^9/L; Total Bilirubin
within normal institutional limits; AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit
of normal; Creatinine =< 1.5 mg/dL OR Creatinine Clearance >= 50 mL/min for patients with
creatinine levels above institutional normal

- Patients enrolled to the Phase 2 portion of the study must have measurable disease by
RECIST criteria

- Ability to understand and the willingness to sign a written informed consent document

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation

- Eligible patients must agree to pre- and post-treatment biopsies of normal skin

- In the phase 1 part of the study, patients with cutaneous disease or accessible lymph
nodes must also agree to pre- and post-treatment tumor biopsies

- In the phase 2 part of the study, tumor biopsies are required of the first 20
patients enrolled who have cutaneous disease or accessible lymph nodes

- Patients must have histologically confirmed, unresectable Stage III or Stage IV
malignant melanoma

- Patients must have received no more than one prior cytotoxic chemotherapycontaining
regimen for metastatic disease and no more than 2 prior treatment regimens overall
for metastatic disease

- ECOG performance status =< 1

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 3 weeks earlier

- Patients may not be receiving any other investigational agents

- Uncontrolled intercurrent illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Patients with other currently active malignancies are excluded, except those with an
in-situ cancer or basal or squamous cell carcinoma of the skin

- In the phase 2 part of the study, patients who have received prior investigational
treatment with a cdk inhibitor are excluded

- Patients with active CNS metastases are excluded

- Patients with a history of CNS metastases that have been treated must be stable for 4
weeks after completion of treatment, with image documentation required

- Patients must not be taking enzyme-inducing anticonvulsants and must be either off
steroids or be receiving a stable dose of steroids

- Pregnant women are excluded from this study because SCH727965 is an agent with the
potential for teratogenic or abortifacient effects

- Breastfeeding should be discontinued if the mother is treated with SCH727965

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with SCH727965