Phase II Study of Cabazitaxel-XRP6258 in Advanced Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer death worldwide and in the United States. The majority of lung cancers are non-small cell lung cancer (NSCLC). The majority of NSCLC cases are advanced at the time of diagnosis. Chemotherapy has improved overall survival but remains limited at \< 12 months median overall survival. New approaches are needed for second line chemotherapy treatment. Cabazitaxel-XRP6258 has shown increased overall survival in metastatic prostate cancer and it is hopeful it can do the same in advanced NSCLC.

A substantial number of patients with lung cancer progress after first line treatment and require second line chemotherapy. Lung cancer appears to account for 40-50% of all known brain metastasis. The incidence of brain metastases among lung cancer patients ranges from 16-20%. Chemotherapy has had limited utility due to problems crossing the blood brain barrier.

Currently there are three drugs approved by the FDA for second line treatment of NSCLC but each has distinct toxicities. Cabazitaxel-XRP6258 is a potent novel taxane with enhanced activity against an increased number of cell lines including lung, prostate, colon, pancreas, head and neck, kidney, gastric, glioblastoma, and melanoma. It also has the ability to cross the blood brain barrier. Cabazitaxel-XRP6258 was found to have an improved antiproliferative activity than other chemotherapy agents against insensitive cell lines. The Phase I studies of Cabazitaxel-SRP6258 have determined dosage and schedule recommendations in advanced NSCLC patients to be utilized for a Phase II multicenter study.

Subjects will be placed on one of two schedules (A or B) each with a specified dosage and administration schedule. All subjects will be followed for survival/progression after every 2 cycles of therapy with imaging studies. A two stage design will be used for each of the two schedules. Fourteen subjects will be accrued for each schedule in the first stage with possible accrual of an additional 34 subjects per schedule depending upon the first stage results.

Eligibility Criteria:
Inclusion Criteria:

* Histologic or cytologic diagnosis of NSCLC (squamous or non-squamous or NSCLC-not specified)
* Subjects who have failed first line chemotherapy (platinum doublets or non- platinum doublets \[previous taxane exposure is allowed\]) for Stage IV NSCLC.
* Measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST)
* Eastern Cooperative Oncology Group (ECOG) performance status 0-2
* Age \> 18 years old
* Adequate bone marrow, liver and renal function, defined as:

  * Absolute neutrophil count (ANC) greater than or equal to 1500/ul
  * Hemoglobin greater than or equal to 10 g/dl
  * Platelet count greater than or equal to 100,000/ul
  * Total bilirubin less than or equal to 1.5 x upper limit of normal (except in subjects with documented Gilbert's syndrome)
  * AST/ALT less than or equal to 1.5 x upper limit of normal
  * Serum creatinine less than or equal to 1.8 mg/dl
* Fully recovered from any previous surgery (at least 4 weeks since major surgery)
* Fully recovered from previous radiation therapy (at least 2 weeks)
* All subjects must agree to practice approved methods of birth control (if applicable). A negative pregnancy test must be documented during the screening period for women of childbearing potential.
* Written informed consent and authorization to use and disclose health information (HIPAA) must be signed by the subject.
* Subjects with symptomatic brain metastases should be adequately treated and controlled prior to the initiation of the study. Subjects with asymptomatic brain metastases will be allowed in the study without any prior therapy for brain metastases.

Exclusion Criteria:

* Concurrent cancer chemotherapy, biologic therapy or radiotherapy
* Administration of any investigational agent within 28 days prior to administration of current therapy
* Untreated symptomatic brain metastases
* Greater than or equal to Grade 2 neuropathy
* Concurrent serious infection
* Concomitant severe or uncontrolled underlying medical disease unrelated to the tumor, which is likely to compromise subject safety and affect the outcome of the study.
* Treatment for a cancer other the NSCLC within 5 years prior to enrollment, with the exception of basal cell carcinoma or carcinoma in situ of the cervix
* Any evidence of history of hypersensitivity for the taxane class of chemotherapy drugs
* History of positive serology for HIV
* Psychiatric disorder that prevents subjects from providing informed consent or following protocol instructions
* Pregnant or lactating women