A Phase I Dose-Escalation Study of CPI-613 (Devimistat) in Combination With Chemoradiation in Patients With Pancreatic Adenocarcinoma
Overview
- Phase
- Phase 1
- Intervention
- CPI-613® (Dose level -1.0 250 mg/m^2)
- Conditions
- Pancreas Adenocarcinoma
- Sponsor
- Medical College of Wisconsin
- Enrollment
- 8
- Locations
- 1
- Primary Endpoint
- Maximum Tolerated Dose of CPI-613®
- Status
- Terminated
- Last Updated
- 5 months ago
Overview
Brief Summary
This is a single-center, open-label, phase I study designed to determine the maximum tolerated dose (MTD) and safety profile of CPI-613® when used concomitantly with chemoradiation for local control of pancreatic adenocarcinoma (PDAC).
Detailed Description
This study is designed to test the hypothesis that a combination of gemcitabine and radiation therapy (Gem-RT) with CPI-613®, a selective mitochondrial metabolism inhibitor in PDAC tumor cells, will be well tolerated without additional significant toxicity. Additionally, CPI-613® is expected to improve the Gem-RT effectiveness, resulting in durable local control of disease. As a necessary and initial step to translate preclinical observations into a patient setting and test our proposed hypotheses, the investigators will perform a dose-finding phase I clinical trial that has been designed to evaluate the maximum tolerated dose (MTD), recommended phase II dose (RP2D), and safety profile of CPI-613® along with standard of care Gem-RT in patients with unresectable PDAC in need of definitive local control of disease. The overarching goals for this trial are to determine the safety and toxicity of CPI-613® when given concurrently with Gem-RT.
Investigators
Mandana Kamgar, MD
Assistant Professor
Medical College of Wisconsin
Eligibility Criteria
Inclusion Criteria
- •Age ≥ 18 years.
- •Pathologically confirmed (histologic or cytologic) adenocarcinoma of the pancreas.
- •Patients should have an inoperable disease (locally advanced, oligometastatic, or medically inoperable) and, based on the review of the institutional pancreatic tumor board, should otherwise benefit from chemoradiation for definitive local control of the primary tumor.
- •Patients with and without regional adenopathy are eligible.
- •History/physical examination, including a collection of weight and vital signs, within 30 days prior to treatment.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-2 within 14 days of study entry.
- •Imaging requirements are to include
- •Diagnostic abdominal/pelvic CT with IV contrast or abdominopelvic magnetic resonance (MR) scan with perfusion and diffusion-weighted sequences within 45 days prior to study entry.
- •Chest CT scan or X-ray within 45 days prior to study entry.
- •Radiation treatment planning abdominal CT. A recommended abdominal MR will be done as a simulation (SIM) scan with interpretation. The CT SIM will not be done with interpretation. Positron emission tomography (PET) scan and MRI are both optional but encouraged. Abdominal MR scans for staging and radiation planning and follow-up are optional but encouraged.
Exclusion Criteria
- •Prior invasive malignancy (except nonmelanomatous skin cancer, noninvasive breast cancer \[ductal carcinoma in situ\], or prostate cancer under active surveillance). Other malignancies are allowed if the patient has been disease free for a minimum of two years.
- •Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
- •Any major surgery within 28 days prior to study entry, except colonic stent placement, intestinal diversion without resection, exploratory laparotomy and laparoscopy or vascular access insertion.
- •Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception during the course of the study and for women three months after study therapy is completed and for men six months after study therapy is completed. This exclusion is necessary because the treatment involved in this study may be significantly teratogenic.
- •Life expectancy less than two months.
- •Severe, active co-morbidity, defined as follows:
- •Any unresolved bowel or bile duct obstruction, or
- •Symptomatic myocardial ischemia, or
- •uncontrolled clinically significant conduction abnormalities (e.g., ventricular tachycardia on antiarrhythmics is excluded and first-degree atrioventricular (AV) block or asymptomatic left anterior fascicular block (LAFB) / right bundle branch block (RBBB) will not be excluded), or
- •Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose
Arms & Interventions
CPI-613® (Dose level -1.0 250 mg/m^2)
Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.
Intervention: CPI-613® (Dose level -1.0 250 mg/m^2)
CPI-613® (Dose level -1.0 250 mg/m^2)
Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.
Intervention: Gemcitabine
CPI-613® (Dose level -1.0 250 mg/m^2)
Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.
Intervention: Intensity-modulated Radiation Therapy
CPI-613® (Dose level 1.0 500 mg/m^2)
Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.
Intervention: CPI-613® (Dose level 1.0 500 mg/m^2)
CPI-613® (Dose level 1.0 500 mg/m^2)
Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.
Intervention: Gemcitabine
CPI-613® (Dose level 1.0 500 mg/m^2)
Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.
Intervention: Intensity-modulated Radiation Therapy
CPI-613® (Dose level 2.0 1,000 mg/m^2)
Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.
Intervention: CPI-613® (Dose level 2.0 1,000 mg/m^2)
CPI-613® (Dose level 2.0 1,000 mg/m^2)
Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.
Intervention: Gemcitabine
CPI-613® (Dose level 2.0 1,000 mg/m^2)
Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.
Intervention: Intensity-modulated Radiation Therapy
CPI-613® (Dose level 3.0 1,500 mg/m^2)
Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.
Intervention: CPI-613® (Dose level 3.0 1,500 mg/m^2)
CPI-613® (Dose level 3.0 1,500 mg/m^2)
Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.
Intervention: Gemcitabine
CPI-613® (Dose level 3.0 1,500 mg/m^2)
Dose escalation/de-escalation for CPI-613® (devimistat) will be conducted using a Bayesian optimal interval (BOIN) design. Gemcitabine will be infused over 30 minutes at a fixed dose of 400 mg/m\^2 weekly. Intensity-modulated radiation therapy will be administered at 54 Gy in 30 fractions of 1.8 Gy per fraction, with five fractions given per week. CPI-613® will be given once per week by IV infusion.
Intervention: Intensity-modulated Radiation Therapy
CPI-613® Maximum Tolerated Dose (MTD)
MTD of CPI-613® from initiation of treatment to 30 days after treatment. MTD will be determined by testing increasing doses of CPI-613®, starting from 500 mg/m\^2 and up to 1,500 mg/m\^2, on dose escalation cohorts of three patients (maximum 24 patients) in combination with Gem-RT therapy. MTD reflects the highest drug dose that does not cause unacceptable adverse effects, with a target dose-limiting toxicity (DLT) rate of 30%. Final dose will be revised as appropriate.
Intervention: CPI-613® (Dose level -1.0 250 mg/m^2)
CPI-613® Maximum Tolerated Dose (MTD)
MTD of CPI-613® from initiation of treatment to 30 days after treatment. MTD will be determined by testing increasing doses of CPI-613®, starting from 500 mg/m\^2 and up to 1,500 mg/m\^2, on dose escalation cohorts of three patients (maximum 24 patients) in combination with Gem-RT therapy. MTD reflects the highest drug dose that does not cause unacceptable adverse effects, with a target dose-limiting toxicity (DLT) rate of 30%. Final dose will be revised as appropriate.
Intervention: CPI-613® (Dose level 1.0 500 mg/m^2)
CPI-613® Maximum Tolerated Dose (MTD)
MTD of CPI-613® from initiation of treatment to 30 days after treatment. MTD will be determined by testing increasing doses of CPI-613®, starting from 500 mg/m\^2 and up to 1,500 mg/m\^2, on dose escalation cohorts of three patients (maximum 24 patients) in combination with Gem-RT therapy. MTD reflects the highest drug dose that does not cause unacceptable adverse effects, with a target dose-limiting toxicity (DLT) rate of 30%. Final dose will be revised as appropriate.
Intervention: CPI-613® (Dose level 2.0 1,000 mg/m^2)
CPI-613® Maximum Tolerated Dose (MTD)
MTD of CPI-613® from initiation of treatment to 30 days after treatment. MTD will be determined by testing increasing doses of CPI-613®, starting from 500 mg/m\^2 and up to 1,500 mg/m\^2, on dose escalation cohorts of three patients (maximum 24 patients) in combination with Gem-RT therapy. MTD reflects the highest drug dose that does not cause unacceptable adverse effects, with a target dose-limiting toxicity (DLT) rate of 30%. Final dose will be revised as appropriate.
Intervention: CPI-613® (Dose level 3.0 1,500 mg/m^2)
CPI-613® Maximum Tolerated Dose (MTD)
MTD of CPI-613® from initiation of treatment to 30 days after treatment. MTD will be determined by testing increasing doses of CPI-613®, starting from 500 mg/m\^2 and up to 1,500 mg/m\^2, on dose escalation cohorts of three patients (maximum 24 patients) in combination with Gem-RT therapy. MTD reflects the highest drug dose that does not cause unacceptable adverse effects, with a target dose-limiting toxicity (DLT) rate of 30%. Final dose will be revised as appropriate.
Intervention: CPI-613® Maximum Tolerated Dose (MTD)
CPI-613® Maximum Tolerated Dose (MTD)
MTD of CPI-613® from initiation of treatment to 30 days after treatment. MTD will be determined by testing increasing doses of CPI-613®, starting from 500 mg/m\^2 and up to 1,500 mg/m\^2, on dose escalation cohorts of three patients (maximum 24 patients) in combination with Gem-RT therapy. MTD reflects the highest drug dose that does not cause unacceptable adverse effects, with a target dose-limiting toxicity (DLT) rate of 30%. Final dose will be revised as appropriate.
Intervention: Gemcitabine
CPI-613® Maximum Tolerated Dose (MTD)
MTD of CPI-613® from initiation of treatment to 30 days after treatment. MTD will be determined by testing increasing doses of CPI-613®, starting from 500 mg/m\^2 and up to 1,500 mg/m\^2, on dose escalation cohorts of three patients (maximum 24 patients) in combination with Gem-RT therapy. MTD reflects the highest drug dose that does not cause unacceptable adverse effects, with a target dose-limiting toxicity (DLT) rate of 30%. Final dose will be revised as appropriate.
Intervention: Intensity-modulated Radiation Therapy
Outcomes
Primary Outcomes
Maximum Tolerated Dose of CPI-613®
Time Frame: Initiation of treatment to 30 days after treatment
MTD will be determined by testing increasing doses of CPI-613®, starting from 500 mg/m\^2 and up to 1,500 mg/m\^2, on dose escalation cohorts of three patients (maximum 24 patients) in combination with Gem-RT therapy. MTD reflects the highest drug dose that does not cause unacceptable adverse effects.
Secondary Outcomes
- The number of subjects with adverse events related to the treatment(Start of study treatment until 30 days after completion of study treatment.)