Clinical Trial of ARQ 761 in Advanced Solid Tumors

Primary Objective:

To determine the safety, tolerability and recommended Phase 2 dose (RP2D) of ARQ 761 administered intravenously.

Secondary Objectives:

To determine the pharmacokinetic profile of ARQ 761 To assess the preliminary anti-tumor activity of aRQ 761

This is an open label, dose escalation study of (-)-trans-3-(5,6-dihydro-4H-pyrrolo \[3,2,1-ij\] quinolin-1-yl)-4(1Hindol-3-yl) pyrrolidine-2,5-dione (ARQ) 761. Drug administration regimen was designed in two parts.

Part I is a single-arm, non-randomized dose-escalation study. Part II is a multi-arm, randomized dose-escalation study. It is designed to establish the clinical tolerability and MTD of ARQ 761 and a recommended Phase 2 dose (RP2D). This is the first-in-human study with ARQ 761.

Part I ARQ 761 will be administered intravenously at a starting dose of 195 mg/m2 IV once weekly. A cycle for any patient already enrolled will consist of weekly administration of ARQ 761 with cycles repeated every 4 weeks (28 days).

Part II Alternate dosing regimen of ARQ 761 will be evaluated at a starting dose of 390 mg/m2. ARQ 761 will be administered intravenously at the assigned duration (2 h or 3 h) weekly, biweekly or for two consecutive weeks followed by one week of rest. Patient will be randomized to Arm A, B or C after enrollment.

Depending on toxicities observed, up to seven treatment cohorts will be enrolled with dose escalation occurring by doubling (first escalation) and 40% increments thereafter. If dosing is tolerated at all levels and pharmacokinetic data suggest continued escalation is warranted, additional dose levels will be considered. Patients enrolled and assessed for dose limiting toxicities (DLTs) will be eligible for intra-patient dose escalation.

Pharmacokinetic assessments will be performed on the first and the forth infusion days following the different regimen to maintain continuity among all treatment groups. Safety and tolerability of ARQ 761 will be assessed for the duration of study treatment. Evaluation of potential anti-tumor activity of ARQ 761 will be performed at regular intervals while patients remain on study. Dose escalation of ARQ 761 will proceed until the maximum tolerated dose or recommended Phase 2 dose is reached.

Intra-patient escalation from lower dose levels to successfully administered dose levels will be allowed. In order for patients at lower dose levels to be eligible for dose escalation, they must tolerate therapy without experiencing any DLT. In addition, prior to escalation, a complete cohort of three patients must have completed two cycles of therapy at the higher dose level without experiencing any DLTs. Patients receiving doses of ARQ 761 may be escalated a maximum of two times to the next consecutive cohorts.

Subjects will be enrolled according to a 3+3 dose escalation scheme. Treatment will be staggered such that the first patient treated at each dose level will receive his or her initial infusion at least 1 week prior to subsequent patients in the same cohort. At least 3 patients within a dose cohort must complete the first cycle of therapy prior to enrolling subjects at the next dose level.

Eligibility Criteria:
Inclusion Criteria:

1. Subjects must have a confirmed solid tumor that is metastatic, unresectable or recurrent and for which standard curative or palliative measures do not exist or are no longer effective.
2. Prior and concurrent therapy:

   Chemotherapy: At least four weeks since prior cytotoxic chemotherapy or 6 weeks since nitrosoureas or mitomycin.

   Molecular targeted agents including monoclonal antibodies and tyrosine kinase inhibitors: At least two weeks since last therapy.

   Endocrine therapy: Subject may be remain on LHRH antagonist therapy for prostate cancer if tumor progression has been confirmed.

   Radiotherapy: At least 3 weeks since most recent radiotherapy. Other investigational therapy: At least four weeks since any other investigational therapy.

   Concurrent therapy: No other concurrent anticancer or investigational therapy permitted except as noted above.
3. Measurable disease is not required, but will be evaluated in each subject when possible.
4. Age ≥18 years
5. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
6. Life expectancy ≥ three months.
7. Central venous access, such as a Portacath or Hickman Line.
8. Pretreatment clinical laboratory parameters within 14 days
9. Availability of 10 unstained slides or paraffin-embedded tissue block from archived tumor specimen.
10. Subjects must be recovered from any toxicity related to prior anti-neoplastic therapy (to grade \<1). Patients with CTCAE grade 2 or less sensory neuropathy or any grade alopecia are eligible.

Exclusion Criteria:

1. Subjects who have had cytotoxic chemotherapy or treatment with monoclonal antibodies within 4 weeks, radiotherapy within 3 weeks, or other molecular targeted therapies.
2. Subjects may not be receiving any other investigational agents.
3. Subjects with known untreated brain metastases. Subjects with known, treated brain metastases must be stable with no symptoms for four weeks.
4. Subjects receiving enzyme-inducing antiseizure drugs ("EIASD").
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements.
6. Pregnant women and breastfeeding should be discontinued.
7. Absence of central venous access for administration of the study drug.