Clinical Trial to Find Optimal Regimen of VS-6766 With or Without Defactinib for LGSOC

There is a need for better treatment options that offer higher response rates and less toxicity than the current standards of care for patients with low-grade serous ovarian cancer (LGSOC).

Thus, Rachel N. Grisham, MD, Section Head of Ovarian Cancer at Memorial Sloan Kettering Cancer Center in Manhattan, New York, and colleagues are leading a phase 2 clinical trial RAMP (Raf And Mek Program) 201, which is now enrolling patients, to determine an optimal regimen of VS-6766 alone or in combination with defactinib for the treatment of patients with recurrent LGSOC.

“We hope the RAMP 201 trial will make progress in delivering a novel treatment that may improve patient outcomes, and are very much looking forward to opening this study to patients around the world,” Dr. Grisham.

Limitations to treatment options for LGSOC include poor response rates and toxicity, which make it difficult for patients to stay on treatment long enough to see a potential response. This is an important factor as patients with this slow-growing disease tend to require therapy over a long duration of time.

The Ongoing RAMP 201 Clinical Trial

The randomized, phase 2, RAMP 201 clinical trial is enrolling patients with all forms of recurrent LGSOC, both with and without a KRAS mutation, and will include approximately 100 females aged ≥18 years with histologically confirmed LGSOC.

As part of this study, Dr. Grisham and colleagues will evaluate and assess the safety, tolerability, and preliminary efficacy of VS-6766, a RAF/MEK inhibitor, administered alone or in combination with defactinib, a FAK inhibitor, in patients with LGSOC treated with at least 1 platinum-based regimen and up to 1 RAF/MEK inhibitor therapy.

According to Dr. Grisham, response rates in RAMP 201 will determine which regimen is taken forward into an expansion phase. The trial will also closely monitor potential toxicities and focus on how to best manage patients throughout the trial so that the treatment can be safely administered and so that patients can have the best chance for a durable response.

LGSOC, which comprises 6% to 8% of all ovarian cancers, has a median survival of approximately 10 years and is generally resistant to chemotherapy, said Dr. Grisham, adding that the majority of patients will experience disease recurrence.

The study, which began in December 2020, is built upon the framework of the ongoing phase 1/2 FRAME study, which has shown clinical activity and durable responses with VS-6766 and defactinib for LGSOC.

“We hope to expand upon the positive trends seen in the FRAME study, showing both impressive responses and durable duration of benefits,” Dr. Grisham said.

Expanding Treatment Options for LGSOC

Looking beyond the treatment regimens currently available, Dr. Grisham said that the recent MILO/ENGOT-ov11 and GOG0281 phase 3 studies have shown the promise of single-agent MEK inhibitor therapy in patients with LGSOC.

“We hope that this unique targeted combination therapy of a dual RAF/MEK inhibitor in combination with a FAK inhibitor will allow patients to stay on therapy longer, potentially allowing for greater improvement,” she noted.
In an updated December 2020 read-out of the FRAME study LGSOC cohort (n = 24), the overall response rate (ORR) is 52% (11 of 21 response evaluable patients), with KRAS mutant ORR at 70% (7 of 10 response evaluable patients), KRAS wild-type ORR at 44% (4 of 9 response evaluable patients) and KRAS status undetermined ORR at 0% (0 of 2 response evaluable patients).

As reported previously, the most common side effects seen in the study were rash, creatine kinase elevation, nausea, hyperbilirubinemia and diarrhea, most being NCI CTC grade 1/2 and all were reversible. The data from the LGSOC cohort are anticipated to be presented at a major medical meeting during the second half of 2021.

Of note, the RAMP 201 trial is being conducted at sites across the United States and the European Union in partnership with the US GOG Foundation and the European Network of Gynaecological Oncological Trial Groups (ENGOT).—Emily Bader