Withdrawn (funding issues)
April 25, 2019
May 7, 2020
The primary objective of the pilot study is to determine activity of PAC-1 and nivolumab combination in subjects with metastatic renal cell carcinoma previously treated with immune checkpoint inhibitor therapy as assessed by objective response rate (ORR) using RECIST 1.1 criteria.
PAC-1 in combination with nivolumab: The MTD will be determined using a modified-Fibonacci dose-escalation 3+3 design. This pilot study will evaluate nivolumab in combination with PAC-1 in subjects with metastatic RCC. Nivolumab will be delivered by IV infusion on Day 1 and PAC-1 will be taken orally on Days 1-28 of each 28-day cycle, and response will be evaluated after every 2 cycles. Treatment will continue until disease progression (based on RECIST 1.1 criteria), unacceptable toxicity, subject refusal, or subject death either from progression of disease, the therapy itself, or from other causes. Subjects who voluntarily stop the study, have progressive disease, or unacceptable toxicities will be followed for survival every 3 months for 12 months from start of study medication
|Experimental: Nivolumab and PAC-1
Patient will be accrued and started on dose 1 level of PAC-1 (500 mg). If no DLT is observed in first cycle of therapy (28 days), dose of PAC-1 will be escalated to 625 mg in second cycle of therapy for the same patient. If patient remains on study and has no dose limiting toxicities, then in third cycle, dose will be escalated to 750 mg and continue in following cycles, if no dose adjustment is needed because of toxicities. Nivolumab will be administered by IV infusion at a dose of 480 mg.
See description in Arms/Groups section
1. Age ≥18 years.
2. Histologically or cytologically confirmed renal cell carcinoma.
3. Stage IV disease progressing on prior immune checkpoint inhibitor therapy
4. Patients must have Eastern Cooperative Oncology Group (ECOG) performance status 0-2
5. Patients must have anticipated life expectancy greater than 3 months.
6. Patients must have measurable disease as defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as ≥
20mm with conventional techniques or as ≥10mm with spiral CT scan by RECIST version
1.1 criteria. Baseline measurements and evaluation of all sites of disease must be
obtained within 4 weeks prior to registration.
7. Palliative radiation must have been completed 2 weeks prior to the initiation of study
8. Patient with known brain metastases must have been treated at least 2 weeks prior to
enrollment, be asymptomatic from brain metastases, stable on brain imaging, and not be
receiving a supra-physiologic dose of steroids (>or = 10 mg prednisone daily or
9. Women must not be pregnant and breast-feeding.
- All females of childbearing potential must have a blood test or urine study
within 2 weeks prior to registration to rule out pregnancy.
- Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth
control or be surgically sterile or abstain from heterosexual activity for the
course of the study through 6 months after the last dose of study medication.
Patients of childbearing potential are those who have not been surgically
sterilized or have not been free of menses > 1 year.
10. Male patients who are sexually active with WOCBP must agree to use an adequate method
of contraception or abstain from sexual intercourse for at least one week prior to
starting with the first dose of study therapy through 7 months after the last dose of
11. Required Initial Laboratory Values (tested within 2 weeks prior to registration):
- Leukocytes ≥2000/ μl
- Hemoglobin >9.0 g/dL
- Platelets ≥100,000/ μl
- ANC ≥1,500/ μl
- Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using
the Cockcroft-Gault formula below):
- Female CrCl = (140 - age in years) x weight in kg x 0.85 72 x serum
creatinine in mg/dL
- Male CrCl = (140 - age in years) x weight in kg x 1.00
- Total Bilirubin <1.5 mg/dl (except for subjects with Gilbert Syndrome, who can
have total bilirubin < 3.0 mg/dl)
- SGOT (AST) <2.5 x ULN
- ALP <2.5 x ULN in absence of liver metastases (<5 x ULN if liver metastases
- PTT or=10mg/day
prednisone equivalents) or other immunosuppressive medications within 14 days of study
drug administration. Inhaled or topical steroids and adrenal replacement doses >10 mg
daily prednisone equivalents are permitted in the absence or active autoimmune
3. Active hepatitis B or hepatitis C infection.
4. History of human immunodeficiency virus (HIV) or known acquired immunodeficiency
5. New York Heart Association class III or IV congestive heart failure.
6. Corrected QT interval calculated by Fridericia formula (QTcF) > 500 ms within 14 days
7. Cardiovascular disorders including unstable angina pectoris, clinically-significant
cardiac arrhythmias, myocardial infarction or stroke (including transient ischemic
attack [TIA], or other ischemic event) within 6 months prior to registration.
8. Active infection requiring intravenous systemic treatment.
9. History of organ transplant.
10. Inability to swallow intact tablets.
Principal Investigator: Peter Hurley, MD HealthPartners Institute