Trial of the Combination of Bortezomib and Clofarabine in Adults With Relapsed Solid Tumors

BACKGROUND:

The proteasome inhibitor bortezomib and purine nucleoside metabolic inhibitor clofarabine
demonstrated greater than additive activity in combination 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 bortezomib
and clofarabine in patients with refractory solid tumors, lymphomas, or myelodysplastic
syndromes (MDS)

- To explore the mechanism of action of the bortezomib and clofarabine combination by

examining markers of DNA damage and apoptosis in tumor cells before and after treatment

-To characterize the changes in MDS residual disease burden that occur with bortezomib

and clofarabine treatment

ELIGIBILITY:

- Study participants must have histologically confirmed solid tumors or lymphomas or
myelodysplastic syndromes 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

- No major surgery, radiation, or chemotherapy within 3 weeks prior to entering the study

- Adequate organ function

STUDY DESIGN:

- This is an open-label Phase I trial

- The starting dose of clofarabine will be 1 mg/m2 administered intravenously on days 1
through 5 of a 21-day cycle; bortezomib will be administered at 0.8 mg/m2 subcutaneously
on days 1 and 4 of a 21-day cycle.

- Dose escalation will follow a 3+3 design, with dose limiting toxicities defined during
cycle 1.

- Dose escalation will proceed in cohorts comprised of two separate groups of patients
(one group of patients with solid tumor/lymphoma and one group of patients with MDS),
with at least 1 from each group, until hematologic DLT or the second grade 2 hematologic
toxicity is observed, at which point, dose escalation will proceed separately for two
cohorts: (1) patients with solid tumors/lymphoma and (2) patients with MDS.

- INCLUSION CRITERIA

Patients must have:

3.1.1 Histologically confirmed solid tumors that have progressed on standard therapy known
to prolong survival or for which no standard treatment options exist, or

3.1.1.2 histologically confirmed myelodysplastic syndrome that has progressed on standard
therapy or for which no standard treatment options exist.

3.1.2 Age greater than or equal to18 years.

3.1.3 ECOG performance status less than or equal to 2.

3.1.4 Life expectancy of greater than 3 months

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

- Absolute neutrophil count: greater than or equal to 1,500/mcL for solid tumors and
lymphomas only

- Platelets: greater than or equal to 100,000/mcL for solid tumors and lymphomas only

- 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

creatinine: ess 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 >1.5 mg/dL

3.1.6 Bortezomib and clofarabine 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.

3.1.7 Patients must have completed any chemotherapy, radiation therapy, or biologic therapy
greater than or equal to 3 weeks (or greather than or equal to 5 half-lives, whichever is
shorter) 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 to 1 week from palliative radiation therapy (patients on study may be
eligible for palliative radiotherapy to non-targeted lesions after 2 cycles of therapy at
the PI s discretion). Patients must have recovered to eligibility levels from prior
toxicity or adverse events. Treatment with bisphosphonates is permitted.

EXCLUSION CRITERIA

3.2.1 Sensory/motor neuropathy greater than or equal to Grade 2

3.2.2 QTc interval (Fridericia formula) > 450 msec for men or > 470 msec for women at study
entry; history of congenital long QT syndrome

3.2.3 Patients who are receiving any other investigational agents.

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

3.2.5 History of allergic reactions attributed to compounds of similar chemical or biologic
composition to study drugs. Patients who have previously received either clofarabine or
bortezomib will be excluded as this may affect accurate determination of the MTD.

3.2.6 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.

3.2.7 Pregnant women are excluded from this study because bortezomib and clofarabine 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.

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

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