Low-Grade Serous Ovarian Cancer: Current Research, Treatment Options, and Clinical Trials

Low-grade serous ovarian cancer (LGSOC) research has accelerated dramatically in recent years, offering new hope through innovative treatment approaches and promising clinical trials. 

Dr. Rachel Grisham, a leading gynecologic medical oncologist at Memorial Sloan Kettering Cancer Center, recently shared crucial insights about the current landscape of LGSOC research and what patients need to know about participating in ovarian cancer clinical trials.

Understanding Different Types of Clinical Trials

Before diving into specific LGSOC studies, it’s important to understand how clinical trials work and what each phase means for patients. Generally, new treatments progress from Phase 1 through Phase 3 studies, with each phase serving a different purpose in the development process.

Questions to Ask Before Joining Any Clinical Trial

Before enrolling in any study, patients should have clear answers to these critical questions:

• What are the known and unknown risks of this treatment?
• What’s the likelihood of benefit versus harm?
• What alternatives to this treatment exist?
• How will I and my side effects be monitored and managed?
• What evidence supports the possible benefit of this drug?
• What happens if I can’t tolerate a side effect?
• How does this differ from standard of care?
• What happens if I decide to withdraw my consent?
• What are the long-term follow-up requirements?
• What will my care look like on this trial? How many visits? What happens at each visit (blood draws, infusions, questionnaires)?

Understanding these fundamentals helps patients make informed decisions about trial participation and sets clear expectations for the journey ahead.

Phase 1 Clinical Trials: Safety and Dosing

Phase 1 trials answer fundamental questions: Is the drug safe? Is it tolerated? What are the pharmacokinetics? These studies are typically conducted in healthy volunteers, though oncology Phase 1 trials often enroll cancer patients. The primary focus is short-term safety, and these studies usually run for a shorter duration than later-phase trials.

These trials use dose escalation protocols to determine the maximum tolerated dose and identify at what doses toxicities occur. Phase 1 studies typically involve:

• First-in-human testing or new drug combinations
• Dose escalation studies using a 3+3 design
• Extensive monitoring including pharmacokinetic (PK) analysis
• Small patient populations of 15 to 30 participants

Key questions to ask about Phase 1 trials:

• Has the drug dose been established yet?
• Are there mandatory biopsies?
• Does the sponsor provide travel reimbursement?

Phase 2 Clinical Trials: Measuring Effectiveness

Phase 2 trials are conducted in patients with the target condition—in this case, all participants will have ovarian cancer. These studies enroll several hundred participants and aim to determine both safety and preliminary efficacy using specific endpoints to decide if the drug warrants a larger, more definitive study.

Unlike Phase 1 trials which are usually uncontrolled, Phase 2 studies may be randomized or non-randomized, and blinded or open-label. These studies generally:

• Use the same medicine for all participants
• Enroll 50 to 100 patients
• Focus on efficacy as the primary endpoint
• May still include some PK testing

Phase 3 Clinical Trials: Comparing to Standard Care

Phase 3 trials enroll hundreds to thousands of participants with the goal to confirm efficacy, monitor adverse effects, and compare the new drug to standard care and/or placebo. These studies are nearly always randomized, controlled, and blinded, representing the definitive evidence needed for FDA approval.

Important considerations:

• Randomization ratios: 1:1 or other ratios
• Blinding: Will you know which treatment arm you’re in? Some patients prefer knowing whether they’re receiving the experimental drug or standard care, and this can influence participation decisions
• Crossover opportunities: Can patients switch to experimental treatment if standard care fails?
• Control arm options: What treatments are available if randomized to standard care?
• Payment and coverage: Will the drug be paid for by the sponsor, or does it go through your insurance?
• Multiple locations: Often available at hundreds of sites

Phase 4 Clinical Trials: Post-Approval Monitoring

Phase 4 trials occur after FDA approval and focus on long-term safety in real-world settings. These studies evaluate whether the drug is effective in broader populations and help identify rarer adverse events that may not have appeared in earlier trials. Phase 4 is also the time to determine optimal use strategies and explore other potential indications for the drug.

Current Clinical Trials for LGSOC

Currently, there is no standard first-line treatment for low-grade serous ovarian cancer, making participation in LGSOC clinical trials particularly important for advancing care. Several groundbreaking studies are actively enrolling patients and showing promising results.

The GY019 Trial: Chemotherapy vs. Hormone Therapy

This groundbreaking phase 3 study addresses a fundamental question in LGSOC treatment: Is letrozole non-inferior to chemotherapy? In other words, researchers aim to prove that hormone therapy alone is not unacceptably worse than the standard chemotherapy approach.

This is a non-inferiority trial, not a superiority trial—meaning they’re not trying to prove letrozole is better than chemo, just that it’s not significantly worse. The possible outcomes range from statistically superior to similar efficacy to significantly inferior. If they can prove letrozole isn’t worse than chemotherapy, that would be a major win for patients given the reduced cost and side effects.

Patients with newly diagnosed disease are randomized to receive either:

• Standard approach: Carboplatin and paclitaxel for six cycles followed by maintenance letrozole
• Hormone-only approach: No chemotherapy after surgery, just maintenance letrozole

Expected to complete enrollment soon, this trial could reshape first-line LGSOC treatment.

MEK Inhibitors: Building on Previous Success

Previous studies of single-agent MEK inhibitors showed response rates of 13 to 26% in LGSOC patients, but significant side effects limited their use. About one-third of patients discontinued treatment due to adverse events including:

• Cumulative rash
• Peripheral edema
• Gastrointestinal side effects
• Serious complications like heart failure and vision problems

The RAMP Studies: A New Combination Approach

RAMP 201 Results

This phase 2 study tested the combination of avutometinib and defactinib with promising results:

• Overall response rate: 31%
• KRAS-mutated patients: 44% response rate
• KRAS wild-type patients: 17% response rate
• Median duration of response: 31.1 months

The combination uses intermittent dosing (3 weeks on, 1 week off) to help manage side effects while maintaining efficacy.

RAMP 301: The Phase 3 Trial

Currently enrolling patients, this randomized study compares the avutometinib/defactinib combination to physician’s choice of standard therapy. Key features include:

• Crossover allowed: Patients on standard care can switch if their treatment stops working
• Primary endpoint: Progression-free survival
• All mutation types: Enrolling both KRAS-mutated and wild-type patients

The Chameleon Trial: Bringing New Treatments to Newly Diagnosed Patients

This innovative study tests the combination of avutometinib, defactinib, and letrozole in patients with newly diagnosed advanced LGSOC who either:

• Are not candidates for immediate surgery
• Have suboptimal surgical outcomes

The goal is to shrink tumors before surgery and continue treatment as maintenance therapy.

Understanding Treatment Response Measurement

Clinical trials use RECIST 1.1 criteria to evaluate treatment effectiveness. This standardized system defines:

• Target lesions: Tumors at least 10mm in diameter or lymph nodes at least 15mm
• Partial response: At least 30% reduction in target lesions
• Progressive disease: 20% or more increase in target lesions
• Complete response: All lesions disappear

The Importance of Clinical Trial Participation

Every person who participates in ovarian cancer clinical trials contributes vital information that advances treatment for future patients. 

As Dr. Grisham emphasized, patients on clinical trials receive incredibly close monitoring from both their regular clinical team and dedicated research teams.

Looking Ahead: The Future of LGSOC Treatment

While we don’t yet have standard first-line treatments specifically for LGSOC, the research pipeline shows tremendous promise. The combination of avutometinib and defactinib represents a potential breakthrough, especially for patients with KRAS mutations, but research continues to benefit all LGSOC patients regardless of mutation status.

For patients considering clinical trials, the key is to start conversations early and ask detailed questions about study design, potential benefits, and practical considerations like travel and time commitments. With continued research participation and advocacy, the outlook for LGSOC patients continues to improve.