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PRI-724

Anthony El-Khoueiry, MD

PRI-724 is a new investigational drug being studied to treat subjects with cancer who have advanced solid tumors. PRI-724 is thought to work by blocking the Wnt signaling pathway that cancer cells need to grow and spread(metastasize).

Phase Ia: Patient cohorts with solid tumor malignancies will be treated with escalating doses (per cohort) of PRI-724 in order to identify the MTD of this single-agent regimen. PRI-724 dosing is to start at 40 mg/m2/day, CIV infusion over 24 hours × 7 days.

Phase Ib: This phase is to begin upon identification of the MTD in Phase 1a. Patient cohorts with CRC will be treated with escalating doses (per cohort) of PRI-724 administered in combination with a modified regimen of FOLFOX6 (mFOLFOX 6, standardized doses and schedule) in order to identify the MTD of this combined regimen. Up to 2 dose levels of PRI-724 are to be examined (640 and 905 mg/m2/day, CIV infusion over 24 hours × 7 days), with potential to evaluate a previously unexamined intermediate dose, if indicated, to more fully characterize tolerability. The MTD cohort (or maximum dose to be studied) will be expanded up to 12 patients.

Primary Objectives

* Determine the MTD of PRI-724 when administered as a 7-day CIV intravenous infusion to patients with solid tumors (Phase Ia).
* Determine the MTD of PRI-724 when administered as a 7-day CIV infusion in combination with mFOLFOX6 in patients with colorectal carcinoma (Phase Ib).

Secondary Objectives

* Describe the dose-limiting toxicities (DLTs) and adverse event profile of PRI-724 when administered as a 7-day CIV infusion either alone in patients with solid tumors, or in combination with mFOLFOX6 in patients with colorectal carcinoma.
* Determine the pharmacokinetic (PK) profile of PRI-724 and C-82 when administered as a 7-day CIV infusion in these patient populations (In Phase 1b PK assessments will not be performed in expanded MTD cohort patients).
* Obtain preliminary assessment of anti-tumor activity as manifested by responses to treatment in these patient populations.
* Measure the mRNA expression of survivin by reverse transcriptase-polymerase chain reaction (RT-PCR), pre- and post-treatment with PRI-724:

  * In circulating tumor cells (CTC)
  * In tumor biopsy specimens from CRC patients (Phase Ib only) Also, evaluate whether survivin expression in CTC is consistent and reflective of expression in tumor specimens.
* Obtain preliminary assessments of potential associations of survivin that may be impacted by the pharmacodynamic (PD) properties of PRI-724 and clinical outcome, toxicity and PK parameters
* Assess the effects of Wnt inhibitor C-82 on the hair follicle neogenesis and the amount of collagen expression

Exploratory Objective

• Obtain matrix metalloproteinase-7 (MMP7) levels in serum via enzyme-linked immunosorbent assay (ELISA) testing

Study Design:

During the Phase Ia portion, an accelerated titration design, specifically, design 4A (no within-patient dose escalation) will be used, and will begin at the starting dose of 40 mg/m2/day. This involves an initial accelerated (double-step) dose escalation phase followed by a standard 3+3 design (single-step) dose escalation phase. In the initial accelerated phase, cohorts of one new patient will be treated per dose level and double-step dose escalations will be used. The accelerated phase will end when the first instance of DLT is observed during any cycle of treatment, or when a second patient experiences a moderate toxicity (MT) during any cycle. The cohort at the current dose level will be expanded and the standard 3+3 design phase (single-step) dose escalation will start for all subsequent cohorts.

In this study, the accelerated phase will end with Dose Level 9 (640 mg/m2/day), unless the toxicity criteria for terminating the accelerated phase are met earlier.

During the accelerated phase, decisions to escalate, expand, or de-escalate will be made when all patients at the current dose level have completed one cycle (2 weeks) of PRI-724, and have received at least 75% of the planned PRI-724 dose, or have experienced a MT or DLT.

During the standard 3+3 phase, decisions to escalate, expand, or de-escalate will be made when all patients at the current dose level have completed two cycles (4 weeks) of PRI-724 and have received at least 75% of the planned PRI-724 dose, or have experienced DLT.

During the Phase Ib portion, dose escalation in patients with CRC will begin at Level 9 of the doses evaluated during Phase Ia (640 mg/m2/day). Up to 2 dose levels will be evaluated (640 and 905mg/m2/day; potential to evaluate a previously unexamined intermediate dose, if indicated) using a standard 3+3 design (single-step dose escalation). Decisions to escalate, expand, or de-escalate will be made when all patients at the current dose level have completed two cycles (4 weeks) of PRI-724 plus mFOLFOX6 (i.e., 2 courses of PRI-724 and 2 courses of mFOLFOX6), and have received at least 75% of the planned PRI-724 dose, or have experienced a DLT.

In both Phase 1a and Phase 1b, the decision to escalate, expand, or de-escalate a cohort may be made by the Sponsor and the Investigator(s) in the absence of a defined DLT if it is determined that a dose level is impractical due to the frequency or nature of toxicities that do not meet DLT criteria. In such a case when a particular dose is deemed impractical, the next lower dose cohort may be expanded for further investigation. Once additional safety data are available, consideration may be given toward identifying the lower dose as the MTD or recommended Phase 2 dose.

Throughout the study, enrollment will be staggered between the first and second patient in each new cohort, to allow for one cycle (2 weeks) to elapse prior to enrolling the second patient into the cohort.

The following toxicities considered by the Investigator to be at least possibly related to study therapy (or study therapy plus chemotherapy) are defined as DLTs:

Non-Hematological DLTs:

* All Grade 3-4 non-hematologic toxicities that represent a 2 grade increase from baseline, excluding:

  * Untreated or inadequately treated nausea, vomiting and diarrhea
  * Alopecia
  * Grade 3 fatigue that returns to Grade 2 or lower within 7 days
* Grade 3 laboratory and/or metabolic abnormalities that do not return to Grade 2 or lower within 72 hours despite treatment
* QTcF \> 500 msec OR an increase in QTc by 60 msec from baseline

Hematologic DLTs:

* Grade 4 neutropenia
* Grade 4 thrombocytopenia
* Neutropenic fever
* ≥ Grade 3 anemia unresponsive to supportive care including blood transfusion and/or erythropoietin therapy
* Grade 3 thrombocytopenia with clinically significant bleeding The DLT observation period, measured from the start of the infusion on the first day, is 2 weeks for the accelerated phase in the Phase Ia portion, and 4 weeks for the 3 + 3 phase in both the Phase Ia and Phase Ib portions of the trial.

Moderate toxicity (MT) is defined as any ≥ Grade 2 toxicity (except alopecia) that is considered by the Investigator to be at least possibly related to the study therapy and that does not qualify as a DLT.

During the Phase Ia portion, MTD is defined as the highest dose level tested in which no patient or only 1 patient experienced a DLT attributable to the study drug(s), when at least 6 patients were treated at that dose and are evaluable for toxicity. The MTD is one dose level below the maximally administered dose (MAD), which is the lowest dose level tested in which 2 or more patients experienced a DLT attributable to the study drug(s). In Phase Ia at least 6 patients will be treated at the MTD.

During the Phase Ib portion, the MTD is defined as the highest dose level tested in which no patient or only 1 patient experienced a DLT attributable to the study drug(s), when at least 6 patients were treated at that dose and are evaluable for toxicity, or when \< 33.3% of patients experienced a DLT attributable to the study drug(s) when 7 to 12 patients were treated at that dose and are evaluable for toxicity. (This would allow for up to 2 DLTs when 7 to 9 patients have been enrolled in the expansion cohort or up to 3 DLTs when 10 to 12 patients have been enrolled in the expansion cohort.) The MTD is one dose level below the MAD which is the lowest dose tested in which\> 1 patient in a 3- to 6-patient cohort, or \> 33.3% of patients in an expanded 7- to 12-patient cohort, experienced a DLT attributable to the study drug(s). In Phase Ib at least 12 patients will be treated at the MTD.

There is potential for expansion of a lower dose cohort up to 12 patients if the initially identified and expanded MTD cohort is found to exceed tolerability.

Safety and Efficacy Study of PRI-724 in Subjects With Advanced Solid Tumors

A Phase Ia/Ib Clinical Trial of PRI-724 in Patients With Advanced Solid Tumors

Maximum Therapeutic Dose (MTD) will be the highest dose in which no dose limiting toxicity (DLT) is seen in a accelerated enrollment cohort (1 patient) and then subsequently a 3-6 patient cohort following a 3+3 study design. MTD may also be determined by evaluation of PK and PD results of patients.

Maximum Therapeutic Dose (MTD) of the combined regimen will be the highest dose in which MTD is defined as the highest dose level tested in which no patient or only 1 patient experienced a DLT in a 3-6 patient cohort or less than 33.3% of 7 - 12 patients experienced a DLT in the 12-patient expansion cohort. MTD may also be determined by evaluation of PK and PD results of patients.

inVentiv Health Clinical

Prism Pharma Co., Ltd.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Safety and Efficacy Study of PRI-724 in Subjects With Advanced Solid Tumors	NCT01302405	Advanced Solid ...	PRI-724	18 Years -	Prism Pharma Co., Ltd.
Safety and Efficacy Study of PRI-724 in Subjects With Advanced Solid Tumors	NCT01302405	Advanced Solid ...	PRI-724	18 Years -	Prism Pharma Co., Ltd.

Spots Global Cancer Trial Database for unresectable neoplastic disease