Combination Nilotinib and Paclitaxel in Adults With Relapsed Solid Tumors

Background:

-The BCR-Abl kinase inhibitor nilotinib demonstrated greater than additive activity in
combination with the anti-tubulin agent paclitaxel in preclinical xenograft models,
justifying the clinical evaluation of this combination for its antitumor activity

Objectives:

- To establish the safety, tolerability, and maximum tolerated dose (MTD) of nilotinib
plus paclitaxel in patients with refractory solid tumors

- To determine the pharmacokinetics of paclitaxel when administered in combination with
nilotinib

- To evaluate the pharmacodynamic effects of the combination on biomarkers of apoptosis,
DNA damage response, and epithelial-to-mesenchymal transition

Eligibility:

- Study participants must have histologically confirmed solid tumor that has progressed on
standard therapy known to prolong survival or for which no standard treatment options
exist

- Age greater than or equal to 18

- No major surgery, radiation, or chemotherapy within 3 weeks prior to entering the study
(6 weeks for nitrosoureas and mitomycin C).

- Adequate organ function

Study Design:

- This is an open-label Phase I trial

- The starting dose of nilotinib will be administered at 300 mg orally BID from cycle 1
day 2 and paclitaxel will be administered IV at 60 mg/m2 at dose level 1 on Days 1, 8,
and 15 in 28-day cycles. For cycle 2 on, nilotinib will be administered from day 1. Dose
escalation will follow a 3+3 design, with dose limiting toxicities defined during cycle
1.

- Up to 25 patients will be accrued to a PD expansion phase at the MTD to further assess
pharmacodynamic endpoints in tumor and CTCs.

- INCLUSION CRITERIA:

- Patients must have histologically confirmed solid tumors that have progressed on
standard therapy known to prolong survival or for which no standard treatment options
exist.

- Age greater than or equal to 18 years.

- ECOG performance status less than or equal to 2.

- Life expectancy of greater than 3 months

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

- Absolute neutrophil count greater than or equal to 1,500/mcL

- Platelets greater than or equal to 100,000/mcL

- Total bilirubin less than or equal to 1.5 X institutional ULN

- AST(SGOT)/ALT(SGPT) less than or equal to 3 X institutional upper limit of
normal; 5.0 x ULN in patients with liver metastases

- creatinine less than or equal to 1.5 X institutional ULN OR

- creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for patients with
creatinine levels greater than 1.5 mg/dL

- Nilotinib and paclitaxel have both been assigned to pregnancy category D by the FDA.
For this reason, 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 and for at least 3 months after
dosing with study drugs ceases. Should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately. Men treated or enrolled on this protocol must also
agree to use adequate contraception prior to the study, for the duration of study
participation, and 3 months after completion of study drug administration.

- Patients must have completed radiation therapy, or major surgery greater than or equal
to 3 weeks, or biologic therapy or chemotherapy greater than or equal to 5 half-lives
or 3 weeks, whichever is shorter (6 weeks for nitrosoureas and mitomycin C) prior to
entering the study. Patients must be greater than or equal to 2 weeks since any prior
administration of a study drug in a Phase 0 or equivalent study and be greater than or
equal to1 week from palliative radiation therapy. Patients must have recovered to
eligibility levels from prior toxicity or adverse events. Treatment with
bisphosphonates is permitted.

- For the PD-expansion cohort, patients must be willing to give biopsies for research
and have tumors amenable for the acceptable biopsy procedures.

EXCLUSION CRITERIA:

- QTcF interval of less than 450 msec at study entry; congenital long QT syndrome

- Sensory/motor neuropathy less than or equal to Grade 2

- Patients who are receiving any other investigational agents.

- Patients with active brain metastases or carcinomatous meningitis are excluded from
this clinical trial. Patients with treated brain metastases, whose brain metastatic
disease has remained stable for less than or equal to 4 weeks without requiring
steroid and anti-seizure medication are eligible to participate.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to study drugs.

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

- Pregnant women are excluded from this study because nilotinib and paclitaxel have been
assigned to pregnancy category D by the FDA. Because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother with
the study drugs, breastfeeding should be discontinued prior to the first dose of study
drug and women should refrain from nursing throughout the treatment period and for 3
months following the last dose of study drug.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
possible PK interactions with study drugs.

- Both men and women of all races and ethnic groups are eligible for this trial.