A Phase I dose escalation study of ARQ 761 (Beta-Lapachone) in adult patients with advanced solid tumors

Summary

This is an open label, dose escalation study of aRQ 761. Drug administration regimen was designed in two parts.

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 regimens 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.


Pharmacokinetic assessments will be performed on days 1 and 22 of the first cycle. 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 weekly 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.

Participant Eligibility

1.Subjects must have a histologically or cytologically 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.

Palliative radiotherapy to localized symptomatic lesions is acceptable while the subject is on study: ARQ761 may be restarted at least one week after completion of RT and recovery from associated toxicities. Irradiated lesions will not be evaluable for response.

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 as defined by (RECIST)RECIST 1.1 (Appendix D)is required.

4.Age >=18 years. Dosing and adverse event data are currently available on the use of ARQ 501 in adults, and toxicology data with ARQ 761 is available only from studies of adult animals. Children are therefore excluded from this study.
5.ECOG performance status <= 1 (see Appendix A).
6.Life expectancy >= three months.
7.Central venous access, such as a Portacath or Hickman Line. [Central access is required because (1) animal safety studies showed local hemorrhage and infusion site necrosis upon repeated dosing and (2) repeated peripheral dosing of ARQ 501 was not tolerated.]
8.Pretreatment clinical laboratory parameters within 14 days of study entry as follows:
*Hemoglobin >= 10 g/dl
*Absolute neutrophil count (ANC) >= 1,500/[MICRO-SYMBOL]L
*Platelets >= 100,000/[MICRO-SYMBOL]L
*Total bilirubin < ULN
*AST (SGOT) & ALT (SGPT) <= 2.5 x institutional ULN in subjects without known liver metastasis; <= 5 x institutional ULN in subjects with known liver metastasis
*Serum creatinine <= 1.5 mg/dl
or
*Creatinine clearance >= 60 mL/min/1.73 m2 for subjects with creatinine levels above institutional normal.

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.


8. 10. Availability of 10 unstained slides or paraffin-embedded tissue block from archived tumor specimen.

11. Enrollment will be restricted to patients demonstrating NQO1 IHC overexpression. Demonstration of NQO1 overexpression by IHC should be confirmed prior to conducting other study procedures (eg, laboratory and imaging studies)