Phase Ib/II Study Reports High Response Rates Seen With Addition of Cisplatin to Regimen for Advanced Pancreatic Cancer


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An 80% response rate with traditional chemotherapy is basically unheard of [in advanced pancreatic cancer]. But we know this is a very small sample, and we are very cautious.
— Gayle Jameson, MSN, ACNP-BC, AOCN

The oncology research team at HonorHealth Research Institute in Scottsdale, Arizona, is spearheading a phase Ib/II trial that is demonstrating promising results with a novel regimen in patients with advanced pancreatic cancer. “The patients we are treating have advanced adenocarcinoma of the pancreas, for which survival is typically very grim,” said principal investigator of the clinical trial Gayle Jameson, MSN, ACNP-BC, AOCN.

“We have added a third drug to the two-drug combination of albumin-bound paclitaxel/gemcitabine, which originated here at our center, and the responses we have seen in the first 10 patients are remarkable in several ways,” she revealed. Albumin-bound paclitaxel, or paclitaxel protein-bound particles for injectable suspension (Abraxane), was formerly known as nab-paclitaxel.

Ms. Jameson and co-investigator Erkut Borazanci, MD, MS, described their study in an interview with The ASCO Post.

Ms. Jameson said they are excited to share positive results in this challenging malignancy. “We want to instill hope, not only in patients but also in physicians, nurses, and oncology teams,” she said. “Many patients come to us for a second opinion, after their oncologist has told them to get their affairs in order. We now have multiple options for stage IV cancer. It’s a new ballgame, and there are choices that patients can make to potentially improve the quantity and quality of their lives.”

Study Details and Rationale

Data available on the first 10 patients were reported at the 2015 American Association for Cancer Research Annual Meeting.1 Based on the encouraging responses observed, the phase II part of the study was expanded to enroll 25 patients, 20 of whom have been treated.

The trial is evaluating a regimen of albumin-bound paclitaxel/gemcitabine plus cisplatin. The choice of cisplatin is based on the recent discovery that pancreatic cancers contain chromosomal aberrations indicative of DNA-repair deficiencies, which are often sensitive to DNA-damaging agents.

“Looking at the genome, we see changes that speak to the fact that there is something related to ‘BRCA-ness’ in pancreatic tumors. The idea is that we can target these global aberrations with DNA-damaging agents, such as cisplatin,” Dr. Borazanci explained.


This treatment requires a lot of attention. In our center, we are very responsive to the needs of our patients. A lot of supportive care is needed around this regimen [of cisplatin plus nab-paclitaxel/gemcitabine].
— Erkut Borazanci, MD, MS

To be eligible for the phase Ib/II study, patients must have stage IV pancreatic cancer and no prior chemotherapy for systemic disease, a Karnofsky performance status ≥ 70, a life expectancy ≥ 12 weeks, and measurable disease.

In phase Ib, patients received albumin-bound paclitaxel at 125 mg/m2 undiluted and gemcitabine at 1,000 mg/m2, each infused over 30 minutes on days 1 and 8 of a 21-day cycle. They also received cisplatin at one of three doses—25, 37.5, or 50 mg/m2—after the albumin-bound paclitaxel infusion. In phase II, all patients will receive cisplatin at 25 mg/m2, which was determined to be the maximum tolerated dose.

Preliminary Results

Of the 10 patients treated in phase Ib, the response rate was 80%, including 2 complete responses (20%), 6 partial responses (60%), 1 patient with stable disease (10%) and 1 patient with progressive disease (10%). “An 80% response rate with traditional chemotherapy is basically unheard of,” Ms. Jameson commented. “But we know this is a very small sample, and we are very cautious. We can’t make big claims based on 10 patients, but we are very encouraged.”

These responses occurred early, by the first staging evaluation, in seven patients. Responses were accompanied by exponential decreases in CA19-9 in the six patients with elevated CA19-9 at baseline. Maximal percentage change from baseline was 40% to 100% for these six patients.

“We saw a very prompt drop in the CA-19 marker and a very rapid response by decreases in RECIST [Response Evaluation Criteria in Solid Tumors] measurements. After three cycles, by 9 weeks, we saw markers plummet and tumors shrink, and we also saw patients feeling better,” Ms. Jameson noted.

Some responses have been durable, she added. “One of our patients with a complete response after 12 cycles is alive 2 years and 3 months after starting this regimen and has no evidence of disease,” she reported. The investigators have not yet reported results for the 20 patients treated in the expanded phase but indicated they “continue to be encouraged.”

Impact of Cisplatin

The ASCO Post asked the investigators to what degree cisplatin added to the benefit seen with standard regimens in this disease.

The phase III MPACT trial established nab-paclitaxel/gemcitabine as first-line treatment, with a 28% reduction in mortality (P < .001) over gemcitabine alone.2 The response rate, by independent review, was 23% with the doublet vs 7% with gemcitabine alone (P < .001).

Similarly, with FOLFIRINOX (fluorouracil/leucovorin/irinotecan/oxaliplatin), the response rate in the pivotal French phase III trial was 31.6% in the FOLFIRINOX group vs 9.4% in the gemcitabine group (P < .001).3 Interestingly, the addition of cisplatin to gemcitabine has not been shown to improve survival in other previous studies.

“This goes back to the idea of building upon other successes. We know that albumin-bound paclitaxel is synergistic with gemcitabine. Based upon genomic research in pancreas cancer,4 we think that the addition of cisplatin may add even greater synergy,” Dr. Borazanci said.

“I don’t want to compare this small population to those other trials, and there are certainly no head-to-head studies, but from what we’re seeing so far, the outcomes in our study are unique,” he said. Ms. Jameson added: “To see 8 of 10 patients do so well has been very exciting.”

Tolerability

“Patients are tolerating the regimen well, but we have a strong focus on supportive care,” said Ms. Jameson. The investigators expected to see more neuropathy and renal toxicity, but so far, the toxicities have not been more than anticipated. “What we actually see is that, because of the rapid response, some patients feel better much more quickly. Several patients who presented with significant pain were able to completely wean off of narcotics,” Ms. Jameson reported.

Adverse events grade ≥ 3 were observed in 60% and ≥ 4, in 30% of patients. Serious adverse events occurred in four patients, including non-neutropenic sepsis/pneumonia, non-neutropenic bacteremia, neutropenic fever/pneumonia, and Clostridium difficile colitis.

Is Regimen Ready for the Clinic?

Ms. Jameson and Dr. Borazanci are aware that oncologists may see these results and try this regimen on their own patients. Those doing so should be aware, said Dr. Borazanci. “This treatment requires a lot of attention. In our center, we are very responsive to the needs of our patients. A lot of supportive care is needed around this regimen,” he noted.

The clinicians’ biggest concerns have been the prevention of dehydration, neuropathy, and fatigue. They use intravenous fluids liberally. “It’s not been completely smooth sailing,” he acknowledged.

Novel Regimen for Stage IV Pancreatic Cancer

  • A phase Ib/II study of 10 patients with advanced pancreatic cancer achieved responses in 80%, including 20% complete responses, using a regimen of albumin-bound paclitaxel/gemcitabine plus cisplatin.
  • The use of cisplatin is based upon the finding of chromosomal aberrations that point to DNA-repair deficiency.
  • The phase II study is enrolling up to 25 patients.

Ms. Jameson emphasized the need to strictly follow the clinical trial protocol. “Our concern is that clinicians may take this regimen and modify it, which would not be advisable,” she said.

The investigators expect to have data from the phase II trial for presentation in 2017. If the phase II results are consistent with the initial findings, they hope to move this regimen forward.

The researchers wanted to credit their funding sources: the Seena Magowitz Foundation, which is dedicated to pancreatic research and treatment, as well as Mattress Firm, which collects public donations for pancreatic cancer research. Stand Up To Cancer funded basic research associated with the project in collaboration with the Translational Genomics Research Institute. ■

Disclosure: Ms. Jameson is on the speakers bureau for Celgene. Dr. Borazanci reported no potential conflicts of interest.

References

1. Jameson GS, Borazanci E, Poplin E, et al: High complete and partial response rate in a phase 1b pilot trial with cisplatin plus albumin-bound paclitaxel and gemcitabine in patients with advanced pancreatic cancer. 2015 AACR Annual Meeting. Abstract LB-003. Presented April 19, 2015.

2. Von Hoff DD, Ervin T, Arena FP, et al: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 369:1691-1703, 2013.

3. Conroy T, Desseigne F, Ychou M, et el: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817-1825, 2011.

4. Ruiz C, Lenkiewicz E, Evers L, et al: Advancing a clinically relevant perspective of the clonal nature of care. Proc Natl Acad Sci U S A 108:12054-12059, 2011.



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