Clinical Trial of ARQ 761 in Advanced Solid Tumors
A Phase 1 Dose Escalation and Pharmacodynamic Study of ARQ 761 (Beta-Lapachone) in Adult Patients With Advanced Solid Tumors
To determine the safety, tolerability and recommended Phase 2 dose (RP2D) of ARQ 761
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 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
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.
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
4. Age ≥18 years
5. 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
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.
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.