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.

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.

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