CC-4047 With Gemcitabine for Untreated Advanced Carcinoma of the Pancreas

A Phase I/II Study of CC-4047 in Combination With Gemcitabine in Subjects With Untreated Advanced Carcinoma of the Pancreas

Because the activity of CC-4047 addresses numerous mechanisms of carcinoma growth inhibition - including, but not limited to anti-angiogenesis - CC-4047 has been selected for development as part of induction chemotherapy regimens for solid tumors. This study in pancreatic cancer is designed to determine the appropriate CC-4047 dose and regimen in combination with gemcitabine.

Phase I

Primary:

• To determine the maximum tolerated dose (MTD) and evaluate the safety profile of oral CC-4047 given on days 1-21 in combination with gemcitabine on days 1, 8, and 15 every 28 days in subjects with advanced pancreatic carcinoma.

Secondary:

• To explore the anti-tumor activity of the combination of CC-4047 and gemcitabine as combination therapy in subjects with advanced pancreatic carcinoma.

Phase II

Primary:

• To explore the anti-tumor activity of the combination of CC-4047 on days 1-21 and gemcitabine on days 1, 8, and 15 every 28 days in subjects with advanced pancreatic carcinoma.

Secondary:

• To evaluate the safety profile of the combination of CC-4047 and gemcitabine as combination therapy in subjects with advanced pancreatic carcinoma.

Inclusion Criteria:

1. Understand and voluntarily sign an informed consent form.
2. Age ≥ 18 years at the time of signing the informed consent form.
3. Must be able to adhere to the study visit schedule and other protocol requirements.
4. Histological or cytological documentation of adenocarcinoma of the pancreas with metastases not amenable to curative surgery or definitive radiation. Patients with locally advanced disease are not eligible.
5. Radiographic or clinical evidence of measurable advanced metastatic pancreatic carcinoma. Subjects must have measurable disease according to the international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee for target lesions (see Appendix 14.2).
6. Subjects may have been previously treated with adjuvant radiation therapy and 5-fluorouracil or Gemzar as a radiosensitizer in the adjuvant setting if they currently have evidence of progression. Following completion of XRT, no further adjuvant chemotherapy with either Gemzar or 5-FU is permitted. No prior Gemzar® for metastatic disease or for primary treatment of locally advanced disease is allowed. Gemzar® used solely as a radiation sensitizer in the adjuvant setting is permitted.
7. ECOG performance status of 0 or 1.
8. Females of childbearing potential (FCBP)† must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL 10 - 14 days prior to and again within 24 hours of starting CC-4047 and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking CC-4047. FCBP must also agree to ongoing pregnancy testing. Men must agree not to father a child and agree to use a condom if his partner is of child bearing potential. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure (see Appendix 14.6).

Exclusion Criteria:

1. Pregnant or lactating females.

2. Any serious medical condition or psychiatric illness that prevents the study subject from signing the informed consent form or places the study subject at an unacceptable risk if he or she participates in the study.

3. Prior therapy with CC-4047, lenalidomide, or thalidomide.

4. Prior use of systemic therapy for the treatment of adenocarcinoma of the pancreas with the exception of 5-fluorouracil or Gemzar® as a radiosensitizer in the adjuvant setting

5. Concurrent use of any other anti-cancer agents.

6. Any of the following laboratory abnormalities:

   • Absolute neutrophil count (ANC) < 1,500 cells/mm3 (1.5 x 109/L)
   • Platelet count < 100,000 cells/ mm3 (100 x 109/L)
   • Serum creatinine > 2.5 mg/dL (221 μmol/L)
   • Serum SGOT/AST or SGPT/ALT > 3.0 x upper limit of normal (ULN); in case of liver metastases > 5 x ULN
   • Serum total bilirubin > 2.0 mg/dL (34 μmol/L)

7. Surgery or radiation therapy within 14 days of study enrollment as outlined below.

   • Surgery within 14 days of the start of study (patients must have recovered from effects of surgery; 7 days may be considered for minor procedures).
   • Palliative radiation therapy within 14 days of the start of study. The radiation therapy may not be to the only site of measurable disease. Adjuvant therapy is permitted in accordance with the inclusion criteria.

8. Prior history of malignancy (except basal cell or squamous cell carcinoma or carcinoma in situ of the cervix or breast, localized prostate cancer with PSA < 1.0 mg/dL) unless the subject has been free of disease for ≥ 3 years.

9. Known brain or leptomeningeal disease (CT scan or MRI of the brain required only in case of clinical suspicion of central nervous system involvement).

10. Grade ≥ 2 neuropathy.