Study design and participants
This phase II Study of Perindopril and Regorafenib in Metastatic Colorectal Cancer (PARICCA) was an open label, single arm trial of patients with refractory mCRC, conducted to measure the incidence and severity of HFSR and hypertension using the CTCAE v4.03 criteria, in patients receiving both regorafenib (160 mg/day) and perindopril (4 mg/day).
Eligible patients had a pathologic documentation of stage IV adenocarcinoma of the colon or rectum and progressed on/after all approved drugs for mCRC including FU-based chemotherapy, oxaliplatin, irinotecan, anti-VEGF therapy, and, if RAS wild type, an anti-EGFR therapy. Patients had to have refractory or progressive disease within 3 months following the last administration of approved standard therapies, or experienced intolerance to previous therapy. Patients treated with oxaliplatin in the adjuvant setting had to progress during or within 6 months of completion of adjuvant therapy. Patients were aged 18 years or older; had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days prior to the initiation of study treatment; life expectancy of at least 3 months; and adequate bone marrow, liver and renal function at the start of the trial. Patients were not eligible if they had previously received regorafenib; had an uncontrolled medical disorder deemed significant by the treating physician; and history of hereditary/idiopathic angioedema, or angioedema related to previous treatment with an ACE inhibitor.
The study was conducted at the BC Cancer Vancouver Center. The University of British Columbia Research Ethics Board approved the protocol, ClinicalTrials.gov Identifier NCT02651415. The trial followed the guiding principles of the Declaration of Helsinki and good clinical practice and complied with all local laws and regulations. Participants provided written informed consent before enrolment; when a patient was not capable of providing a signature, an oral statement of consent could be provided in the presence of a witness.
Study end points
The primary end point was the incidence of all grade toxicities for HFSR defined by CTCAE v4.03 criteria. The incidence of HFSR was expressed as the number of patients experiencing any grade HFSR. The primary end point was a 50% reduction in all grades of HFSR based on CTCAE v4.03 criteria (i.e. from 47% any grade HFSR to 24% of patients).
Secondary end points were the incidence of all grade hypertension and toxicity; maximal severity of HFSR; time to development of stage 3 HFSR; and progression-free survival (PFS). All grades of hypertension were evaluated using CTCAE v4.03, measured weekly for the first 6 weeks while patients were on the study drug, then every second week during treatment with perindopril and during the 30-day follow-up period (post-therapy).
All grades of AE (including HFSR) were evaluated using CTCAE v4.03 at baseline and day 1 of each cycle while they were on the study drug and during the 30-day follow-up period (post-therapy). PFS was evaluated based on RECIST v1.1 criterion, with 20% progression of existing metastases or any new metastases.
Information on previous experience with HFS was collected as per patient recollection only at enrolment (no chart review). This was an exploratory analysis to determine if previous HFS influences the rate and severity of HFSR in this study.
Patients were followed for survival. For subjects who discontinued study treatment and did not experience PD, available tumour assessments were recorded in the CRF until documented PD.
The dose and schedule of regorafenib used in this trial was the approved dose of 160 mg per day from data accumulated in previous regorafenib phase III trials [4, 5]. Perindopril erbumine 4 mg was administered daily for 21 days of a 28–day cycle . Perindopril was administered in the morning on an empty stomach. Regorafenib was administered 160 mg daily for 21 days of a 28–day cycle, with a low fat breakfast 1 h after perindopril. All patients received BSC.
Predefined dose modifications were permitted to manage clinically significant treatment-related AEs. Patients who required dose reductions could re-escalate the dose up to 160 mg daily at the discretion of the investigator once the AE resolved to baseline levels. Treatment was discontinued permanently if the AE did not recover after a 4-week interruption or after dose reduction by two dose levels.
Patients were treated until clinical radiological disease progression based on RECIST v1.1 criterion, death, unacceptable toxicity, withdrawal of consent by the patient, decision by the treating physician that discontinuation would be in the patient’s best interest, or substantial non-compliance with the protocol. If in the investigator’s opinion treatment with regorafenib provided clinical benefit to a patient experiencing disease progression, the patient could continue treatment.
Patients were seen by a physician every week for the first cycle, every 2 weeks for the second cycle, at the start of each subsequent cycle, at the end of treatment, and every month after cessation of treatment until death or data cutoff. ECOG status and concomitant medications were assessed at the start of treatment and at each physician visit. Blood pressure and LFTs were done weekly for the first cycle, on days 1 and 7 in the second cycle, on day 1 of each subsequent cycle, and at the follow-up visit. Lipase, electrolytes, TSH, and chemistry were collected on day 1 of each cycle. CEA, CBC, and creatinine were evaluated on day 1 of each cycle and at the end of treatment. A 12-lead ECG was administered on day 11 of each cycle and at the end of treatment. Other tests were administered as per the standard of care for regorafenib and perindopril. The study protocol mandated a patient education module that included a patient education brochure regarding the management of HFSR and preventative measures to manage this side effect.
Study interim analysis and discontinuation rule
The study was to be discontinued if five of the first ten patients exhibited a Grade 3 HFSR, or if the HFSR was more severe with the addition of perindopril than with regorafenib alone.
Demographic and other baseline characteristics were listed and summarized. Qualitative data were summarized using frequencies and percentages; quantitative data were summarized using descriptive statistics. Secondary safety variables were summarized using descriptive statistics and exploratory graphical presentations of the data. Statistical analyses were performed using SAS 9.3.
The primary analysis set consisted of all evaluable patients. An evaluable patient was defined as an eligible patient who received at least one cycle of study medication. The safety set consisted of all patients who received at least one dose of study medication. RECIST criteria were used by the investigator to determine PFS and OS end points.
Sample size assumptions
A 10% reduction in all grades of HFSR is a clinically meaningful reduction, with an alpha level of 0.05 and a power of 80% for the sample size calculation.