In an interview, Mohamad Adham Salkeni, MD, FRCPC, discussed the ongoing study of maintenance ivaltinostat plus capecitabine or capecitabine monotherapy in patients with metastatic pancreatic adenocarcinoma whose disease has not progressed on first-line FOLFIRINOX.
A phase 1b/2, dose-escalation, randomized, multicenter study is evaluating the efficacy, safety, tolerability, and pharmacokinetics (PK) of ivaltinostat, a histone deacetylase (HDAC) inhibitor in combination with capecitabine vs capecitabine monotherapy in patients with metastatic pancreatic adenocarcinoma whose disease has not progressed on a first line fluoropyrimidine-based chemotherapy.1
Approximately 70 patients, including 18 in the phase 1b dose-escalation, and 52 in phase 2 portion, will be included in the study. Phase 1b will study 3 dose levels of ivaltinostat in combination with a fixed dose of capecitabine to determine the recommended phase 2 dose (RP2D) of ivaltinostat, and phase 2 will assess patients randomized in a 1:1 ratio to receive either ivaltinostat plus capecitabine or capecitabine monotherapy.
In phase 2, capecitabine will be given at a fixed dose of 1000 mg/m2 orally twice daily on days 1 to 14 and the RP2D of ivaltinostat, as determined in phase 1, will be administered via intravenous infusion once a week for 2 weeks, followed by 1 week of rest during the 21-day cycle.
The objectives of phase 1b include determining dose-limiting toxicities (DLTs), safety, tolerability, RP2D, efficacy, and PK profile of ivaltinostat in combination with capecitabine. The primary end point of phase 2 is progression-free survival (PFS) and secondary end points include overall survival (OS), objective response rate (ORR), disease control rate (DCR), and incidence of treatment-emergent adverse events (AEs).
According to Mohamad Adham Salkeni, MD, FRCPC, there has not been significant progress made regarding treatments and outcomes for patients with pancreatic ductal adenocarcinoma in the last 20 years. However, this trial could be an option for patients with metastatic pancreatic adenocarcinoma based on data from early studies evaluating ivaltinostat combinations.
“Enrolling patients in clinical trials as early as possible in their diagnosis is critical, and potentially the only route to find or discover active agents in this aggressive type of cancer,” Salkeni, medical oncologist and clinical trial investigator at the Virginia Cancer Specialists Research Institute, told Targeted OncologyTM, in an interview.
In the interview, Salkeni discussed the ongoing phase 1/2 study of ivaltinostat with capecitabine vs capecitabine alone for the treatment of patients with metastatic pancreatic adenocarcinoma.
Targeted Oncology: Can you discuss ivaltinostat and what rationalizes its use in combination with capecitabine for the treatment of metastatic pancreatic adenocarcinoma?
Salkeni: Ivaltinostat is an HDAC inhibitor. HDAC is an enzyme that is thought to silence key tumor suppressor genes and at the epigenetic level. Epigenetics is machinery of post-translational modification of gene expression. It's been found that in some cancers, epigenetic silencing of a tumor suppressor gene plays a role in oncogenesis. By inhibiting that process, we hope to achieve success in halting tumor growth and reducing risk of progression. Effective HDAC inhibition can make DNA around histone complexes more accessible to transcription and allows suppressed genes to be translated and regain activity.
As a novel drug, ivaltinostat has been granted an orphan drug designation by the FDA. In preclinical models, it has been shown to reduce tumor growth and was found to be synergistic with other chemotherapies, particularly with capecitabine. In a published early phase trial, ivaltinostat demonstrated clinical activity when combined with gemcitabine and erlotinib [Tarceva]. Based on that encouraging preclinical and early phase clinical data, the trial was designed so that it may be an additional therapy for patients who have advanced or metastatic pancreatic adenocarcinoma.
What led to the start of this phase 1/2 study?
Some synergistic activity in combination with capecitabine, and the early phase trial with the combination of gemcitabine and erlotinib. In that early phase trial, 16 patients were treated and evaluated for a treatment response, and there was an observed overall response rate of 25%, with a disease control rate of over 90%.
Based on these earlier promising results, and well-tolerated safety profile, the current trial was designed as an option for maintenance therapy for patients who don't have a lot of options to start with. The trial is essentially a 2-part study with the dose-escalation phase termed phase 1b. We use 3 different increasing doses of ivaltinostat in combination with capecitabine for 2 weeks, followed by a 1-week break within a 21-day cycle. Ivaltinostat is given IV weekly, and the initial phase uses incrementing doses or escalating doses of ivaltinostat in combination with a fixed dose of capecitabine.
Phase 2 is planned to include about 52 additional patients. Patients are randomized to either a combination of ivaltinostat with capecitabine or capecitabine as a single agent. This phase requires patients to have completed a minimum of 16 weeks of 5-Fluorouracil [5FU]-based chemotherapy with no evidence of progression at the end of that 16-week initial treatment. The patients would then be followed for response and clinical benefit with serial scans and tumor marker monitoring. In a nutshell, that is the design of the trial.
What is the status of the study? Do you have any preliminary findings?
The study is currently in the third and final dose escalation part of phase 1b, so it is still early on and we don't yet have survival outcomes The study is open and enrolling at multiple centers across the country, including Virginia Cancer Specialists in Fairfax, Virginia. We are within 30 minutes of DC and we try to make our trials accessible to the local as well as out-of-state communities.
What is the message to community oncologists who may be considering referring their patients to this clinical trial?
Pancreatic adenocarcinoma is one of those tumors that we haven't made a whole lot of progress in the last 20 plus years. Beyond 5FU-based regimens, which produce a response in about a third or less of patients, and gemcitabine plus nab-paclitaxel produces a response in about a fourth or less of patients and a median overall survival of less than 1 year, novel therapies are direly needed at this stage. Enrolling patients in clinical trials as early as possible in their diagnosis is critical, and potentially the only route to find or discover new, effective active agents in this aggressive type of cancer.
Sometimes, patients receive chemotherapy upfront as they're diagnosed, and rarely do patients tolerate a lengthy duration of treatment due to the cumulative nature of adverse effects, particularly the neuropathy, cytopenias, and the overall effect on the body and wellbeing. That's why maintenance therapies come into play here aiming at delaying progression while maintaining a good quality of life. This would be a good option for patients to embark on and delay the time it takes for the tumor to progress or relapse.