A Dose Escalation Trial of PR610 Treating Patients With Solid Tumors

A Phase I/II, Multi-Center, Open-Label, Dose Escalation Trial of the Safety and Pharmacokinetics of Intravenous PR610 Given Weekly in Subjects With Solid Tumors

The purpose of this study is to determine the Maximum Tolerated Dose and the Dose-Limiting Toxicity of the drug to further evaluate safety and antitumor activity.

Study Overview

• Status: Terminated
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Drug: PR610

Detailed Description

Following informed consent, subjects undergo baseline evaluation and disease assessment. PR610 is administered intravenously weekly.

In the absence of progressive disease or unacceptable toxicity, subjects may continue to receive PR610. Intra-subject dose escalation (to no higher than the highest safe level) is allowed in subjects who are not experiencing dose limiting toxicity. Disease assessment will be repeated at week 6 and then every 8 weeks thereafter.

Pharmacokinetic (PK) assessment (PR610 and PR610E) will be performed for all subjects.

After determination of the MTD and the determination of the phase II dose, additional subjects with NSCLC that is genetically resistant to reversible EGFR inhibitors will be accrued into an expansion cohort.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• New Zealand
  • Auckland, New Zealand
    • Auckland City Hospital
  • Waikato, New Zealand
    • Waikato Hospital
• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85258
      • Scottsdale Healthcare
  • California
    • Sacramento, California, United States, 95817
      • University of California-Davis Comprehensive Cancer Ctr
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Robert H. Lurie Comprehensive Cancer Research Center
  • Texas
    • San Antonio, Texas, United States, 78229
      • South Texas Accelerated Research Therapeutics

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed informed consent
• Age 18 years or more

• Histologically-confirmed, progressive cancer with the following diagnosis:

  1. Phase I: locally advanced or metastatic solid tumor that may respond to an EGFR inhibitor;
  2. Phase II: Stage IIIB or IV, non-squamous, non-small cell lung cancer (NSCLC) with known sensitizing mutations in EGFR, and the T790M resistance mutation
• Failed, refused, or not eligible for standard of care therapy
• ECOG performance status of 0, 1, or 2
• Life expectancy of at least 12 weeks
• At least 4 weeks from prior anticancer therapy including chemotherapy, hormonal, investigational, and/or biological therapies and irradiation. Ongoing hormonal therapy administered for control of prostate cancer which may be continued through the study. In addition, in the phase II portion of the study, prior reversible EGFR tyrosine kinase inhibitor therapy, such as erlotinib or gefitinib, may be continued up to 48 hours prior to start of PR610 to prevent significant disease flare.

• Recovered from prior treatment related toxicity

  1. except for grade 1 fatigue, grade 1 peripheral sensory neuropathy and grade 1 or 2 alopecia during the phase I portion of the study
  2. except for grade 1 toxicity, and grade 2 peripheral neuropathy during the phase II portion of the study
• At least four (4) weeks from prior major surgery
• Women of child-bearing potential must be willing to use an acceptable contraceptive method and must have a negative urine or serum pregnancy test within 2 weeks prior to beginning treatment on this trial
• Sexually active men must be willing to use an acceptable contraceptive method
• Adequate hematological and biological function
• Willingness to participate in PK sampling during cycles 1 and 2
• Willingness to provide permission to access archived tumor samples for evaluation of EGFR mutation status
• Willingness to provide samples for storage of normal tissue containing wild-type DNA

Additional Inclusion Criteria during Expansion Phase

• At least one target lesion as defined by RECIST 1.1 that allows for evaluation of tumor response

Exclusion Criteria:

• Pregnant or nursing women
• Any uncontrolled medical illness including, but not limited to, significant gastrointestinal disorders, cardiovascular disease, or interstitial lung disease
• History of clinically significant cardiovascular abnormalities, eg., uncontrolled hypertension, CHF (NYHA classification ≥2), unstable angina, poorly controlled arrhythmias, myocardial infarction within 6 months of study entry, implantable pacemaker or implantable cardioverter defibrillator
• Clinically significant abnormal 12-lead ECG with QTcF >450 msec
• Use of any medications known to produce QT prolongation
• Family history of Long QT Syndrome
• Prior treatment with anthracyclines with a cumulative dose of doxorubicin (or equivalent) ≥400 mg/m2
• Cardiac left ventricular function with resting ejection fraction of less than 50%
• Symptomatic CNS lesions or known CNS lesions that require therapy
• Prior history of an allergic reaction to a tyrosine kinase inhibitor

Additional Exclusion Criteria during Expansion Phase

• Any other malignancy likely to effect the assessment of toxicity or efficacy of PR610

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PR610	Drug: PR610; Dose escalation of PR610 to determine maximum tolerated dose for weekly administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine the Maximum Tolerated Dose (MTD) of PR610 for Both a 1-hour and a 24-hour Weekly IV Infusion	The first cohort of three subjects will receive PR610 at Dose Level 1. Subsequent cohorts will receive PR610 at a dose levels determined as per dose escalation criteria. The MTD will be defined as the dose level at which one (1) or fewer subject in six exhibit DLT with the next highest dose level demonstrating two (2) or more of six (6) subjects with DLT (or for which more than ≥33% of subjects exhibit DLT if the cohort size exceeds 6 subjects).	3 weeks (1 cycle)
Determine the Dose-Limiting Toxicity (DLT) of PR610 for Both a 1-hour and a 24-hour Weekly IV Infusion	DLT is defined as the following: Occurs during the first cycle of PR610; Is considered PR610-related, as defined by "Definitely-related", "Probably-related" or "Possibly-related"; Is clinically significant, as determined by the Principal Investigator In addition, DLT will meet at least one of the criteria listed below using grading criteria from the CTCAEv4.; Grade 4 hematologic toxicity; Any drug-related toxicity that prevents administration of 100% of all doses of PR610 planned for Cycle 1; Grade 3 or higher non-hematologic toxicity	3 weeks (1 Cycle)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the safety profile of PR610: Adverse Events	The number of adverse events experienced by participants will be measured.	30 days following the last administration of study treatment
Peak Plasma Concentration (Cmax) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion		pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2
Evaluate the activity of PR610 in a general phase I population and in a subset of subjects with NSCLC genetically resistant to reversible EGFR inhibitors	Efficacy will be determined for each subject that received at least one dose of PR610 and had at least one post-baseline disease assessment. The following four outcomes will be tabulated: Tumor response Time to response Duration of response Progression-free survival	30 days following the last administration of study treatment
Time of Peak Plasma Concentration (tmax) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion		pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2
Half life (t1/2) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion		pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2
Area Under the Curve (AUC) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion		pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2
Clearance (CL) of PR610 and PR610E for Both a 1-hour and a 24-hour Weekly Infusion		pre, 30 minutes into infusion, end of infusion, 1, 2, 4, 24, 48, and 72 hours post-infusion on Cycles 1 and 2

Collaborators and Investigators

• Sponsor: Proacta, Incorporated
• Investigators: Study Chair: Proacta Inc., Proacta, Incorporated

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Anticipated): March 1, 2015
• Study Completion (Anticipated): August 1, 2015

Study Registration Dates

• First Submitted: June 7, 2012
• First Submitted That Met QC Criteria: June 27, 2012
• First Posted (Estimate): June 29, 2012

Study Record Updates

• Last Update Posted (Estimate): June 16, 2014
• Last Update Submitted That Met QC Criteria: June 13, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: NSCLC; lung cancer; non-small cell lung cancer; solid tumors; non-squamous, non-small cell lung cancer
• Additional Relevant MeSH Terms: Neoplasms
• Other Study ID Numbers: PR610-1001

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No