Abraxane and Alimta in Advanced Solid Tumors

Phase I/II Trial of Abraxane® (ABI-007) and Alimta® (Pemetrexed) in Advanced Solid Tumors With Emphasis on Non-Small Cell Lung Cancer (NSCLC) and Breast Cancer

RATIONALE: Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pemetrexed may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving paclitaxel albumin-stabilized nanoparticle formulation together with pemetrexed may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of paclitaxel albumin-stabilized nanoparticle formulation when given together with pemetrexed and to see how well they work in treating patients with advanced non-small cell lung cancer, breast cancer, or other solid tumors.

OBJECTIVES:

Primary

• Determine the safety of paclitaxel albumin-stabilized nanoparticle formulation when administered with pemetrexed disodium in patients with advanced non-small cell lung cancer, breast cancer, or other solid tumors. (Phase I)
• Determine the efficacy of this regimen, as measured by objective tumor response rate (RECIST criteria), in these patients. (Phase II)

Secondary

• Determine the preliminary efficacy of paclitaxel albumin-stabilized nanoparticle formulation and pemetrexed disodium in these patients. (Phase I)
• Determine the overall survival of patients treated with this regimen. (Phase II)
• Evaluate the frequency and severity of toxicities associated with this regimen. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of paclitaxel albumin-stabilized nanoparticle formulation followed by an open-label, phase II study.

• Phase I: Patients receive pemetrexed disodium IV over 10 minutes and paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of paclitaxel albumin-stabilized nanoparticle formulation until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients receive pemetrexed disodium and paclitaxel albumin-stabilized nanoparticle formulation at the MTD as in phase I.

After completion of study treatment, patients are followed periodically.

Inclusion Criteria

1. For the phase II portion patients must have cytologically or histologically proven selected stage IIIB (pleural effusion) or IV NSCLC.
2. For the phase II portion patients must have NSCLC that has progressed or recurred after treatment with platinum-based therapy.
3. No prior pemetrexed. Prior Taxol is allowed. Prior ABI 007 is not allowed.
4. Patients must have measurable disease by RECIST criteria for the phase II portion.
5. Patients must be 18 years of age or older.
6. Patients must have a performance status of 0 -2
7. Patients must have an estimated survival of at least 3 months.
8. Any prior chemotherapy must have been completed at least 4 weeks prior to start of treatment.
9. Patients must have adequate renal function as documented by a calculated creatinine clearance of > 45 ml/min
10. Patients must have adequate liver functions: AST and ALT < 2.5 X upper limit of normal, and bilirubin < upper limit of normal.
11. Patients must have adequate bone marrow function: Platelets >100,000 cells/mm3 and ANC > 1,500 cells/mm3.
12. For patients who have baseline clinically significant pleural or peritoneal effusions (on the basis of symptoms or clinical examination) before initiation of pemetrexed therapy, consideration should be given to draining the effusion prior to dosing.
13. Patients with asymptomatic treated brain metastasis (surgical resection or radiotherapy) may be included if they are neurologically stable and have been off steroids and anticonvulsants for at least 4 weeks.
14. Patients must be able to take and retain oral medication.
15. Ability to take folic acid, vitamin B12 and dexamethasone according to protocol.
16. Ability to interrupt NSAIDS 2 days before, the day of, and 2 days following administration of pemetrexed.
17. Patients of reproductive potential must agree to use effective contraceptive method while on treatment and for 3 months afterwards as the effects of these drugs on the unborn fetus are unknown.
18. No other current active malignancy.
19. Patient or his/her legally authorized representative or guardian signed the Informed Consent form prior to participation in any study-related activities.

Exclusion Criteria

1. Pregnant or breastfeeding women.
2. Patient with pre-existing peripheral neuropathy of NCI CTCAE Version 3.0 of grade 2.
3. Patient has a clinically significant concurrent illness.
4. Patient is currently enrolled in a different clinical study in which investigational procedures are performed or investigational therapies are administered.
5. Patient has a history of allergy or hypersensitivity to the study drugs or a taxane.
6. Patient has serious medical risk factors involving any of the major organ systems such that the investigator considers it unsafe for the patient to receive an experimental research drug.
7. Prior therapy with pemetrexed, or ABI-007.
8. Patient is receiving treatment with any excluded concomitant medication.
9. Presence of third space fluid which cannot be controlled by drainage.