A Dose Escalation Trial of PR610 Treating Patients With Solid Tumors

Sponsor

Proacta, Incorporated (Industry)

Overall Status

Terminated

CT.gov ID

NCT01631279

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

5.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Unspecified Adult Solid Tumor, Protocol Specific	Drug: PR610	Phase 1/Phase 2

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 Design

Study Type:

Interventional

Actual Enrollment :

33 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Aug 1, 2012

Anticipated Primary Completion Date :

Mar 1, 2015

Anticipated Study Completion Date :

Aug 1, 2015

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: PR610

Drug: PR610

Dose escalation of PR610 to determine maximum tolerated dose for weekly administration

Outcome Measures

Primary Outcome Measures

Determine the Maximum Tolerated Dose (MTD) of PR610 for Both a 1-hour and a 24-hour Weekly IV Infusion [3 weeks (1 cycle)]
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).
Determine the Dose-Limiting Toxicity (DLT) of PR610 for Both a 1-hour and a 24-hour Weekly IV Infusion [3 weeks (1 Cycle)]
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

Secondary Outcome Measures

Evaluate the safety profile of PR610: Adverse Events [30 days following the last administration of study treatment]
The number of adverse events experienced by participants will be measured.
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 [30 days following the last administration of study treatment]
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
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Signed informed consent
Age 18 years or more
Histologically-confirmed, progressive cancer with the following diagnosis:

Phase I: locally advanced or metastatic solid tumor that may respond to an EGFR inhibitor;
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

except for grade 1 fatigue, grade 1 peripheral sensory neuropathy and grade 1 or 2 alopecia during the phase I portion of the study
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Scottsdale Healthcare	Scottsdale	Arizona	United States	85258
2	University of California-Davis Comprehensive Cancer Ctr	Sacramento	California	United States	95817
3	Robert H. Lurie Comprehensive Cancer Research Center	Chicago	Illinois	United States	60611
4	South Texas Accelerated Research Therapeutics	San Antonio	Texas	United States	78229
5	Auckland City Hospital	Auckland		New Zealand
6	Waikato Hospital	Waikato		New Zealand