Vismodegib + Atezolizumab for Ovarian Cancer

Overseen By Lucia Borasso, BSN

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Ronald Buckanovich

Must not be taking: Antibiotics, Immunosuppressants, Immunostimulants, others

Disqualifiers: Autoimmune disease, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 36 months

48 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of combining two drugs, vismodegib and atezolizumab (an immunotherapy drug), in treating certain ovarian cancers that resist standard treatments. These include ovarian, fallopian tube, or primary peritoneal cancer that has become resistant to platinum-based chemotherapy. Individuals whose cancer has progressed within six months after their last platinum-based treatment may qualify. This trial provides an opportunity to explore a new treatment approach when options are limited. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, certain treatments like systemic immunosuppressive medications and systemic immunostimulatory agents must be stopped before starting the trial. It's best to discuss your specific medications with the trial team.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that combining vismodegib and atezolizumab holds promise for treating certain cancers. Atezolizumab boosts the immune system's ability to fight cancer and is generally well tolerated. Patients with advanced ovarian and uterine cancers have used it without new safety concerns, and most side effects were mild.

Vismodegib, the other drug in this combination, has been used in other treatments as well. This trial is in a phase that evaluates the treatment's effectiveness, indicating some prior understanding of its safety.

Both drugs in this trial have undergone previous safety studies. However, since individual responses vary, researchers will closely monitor participants to ensure their safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of vismodegib and atezolizumab for ovarian cancer because it targets the disease in a novel way. Vismodegib works by inhibiting the Hedgehog signaling pathway, a process that is often activated in cancer cells, while atezolizumab is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells more effectively. This dual approach not only targets the cancer cells directly but also enhances the body's immune response against the tumor. Unlike traditional chemotherapy, which attacks all rapidly dividing cells, this combination aims to specifically disrupt cancer growth and boost immune activity, potentially leading to more effective and less toxic treatment outcomes.

What evidence suggests that the combination of vismodegib and atezolizumab could be effective for ovarian cancer?

This trial will evaluate the combination of vismodegib and atezolizumab for treating ovarian cancer that resists standard platinum-based treatments. Research has shown that vismodegib, which blocks a pathway aiding tumor growth, combined with atezolizumab, an immunotherapy that boosts the immune system to fight cancer cells, might enhance treatment effectiveness. Studies suggest this combination could outperform each drug used alone. Early results appear promising, but further research is needed to confirm its efficacy. ^{1 2 3 6 7}

Who Is on the Research Team?

Ronald Buckanovich, MD

Principal Investigator

UPMC Hillman Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with ovarian, fallopian tube, or primary peritoneal cancer that's resistant to platinum-based chemotherapy. Participants need good organ function and blood work within normal ranges, no severe infections or heart issues recently, not on certain medications, and must agree to contraception if applicable. They should have a life expectancy of at least 3 months and an ECOG Performance Status of 0-1.

Inclusion Criteria

Negative HIV test at screening

Ability to comply with the study protocol, in the investigator's judgment

My blood and organs are functioning well.

Exclusion Criteria

Active or history of autoimmune disease or immune deficiency

I am currently on medication for hepatitis B.

I have not received a live vaccine in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a combination of vismodegib and atezolizumab. Vismodegib is administered at a fixed dose of 150 mg PO daily, and Atezolizumab is administered at a fixed dose of 1200 mg on Day 1 of each 21-day cycle.

Up to 36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of objective response rate, progression-free survival, and overall survival.

Up to 36 months

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Vismodegib

Trial Overview The trial tests a combination treatment using Vismodegib and Atezolizumab in patients whose cancer hasn't responded well to platinum-based treatments. The goal is to see if this new approach can improve outcomes since current response rates are low with existing therapies.

How Is the Trial Designed?

Group I: vismodegib + atezolizumab Experimental Treatment 2 Interventions

Vismodegib: fixed dose of 150 mg PO daily Atezolizumab: fixed dose of 1200 mg Q3W (1200 mg on Day 1 of each 21-day cycle)

Atezolizumab is already approved in United States, European Union for the following indications:

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

Ronald Buckanovich

Lead Sponsor

Trials

2

Recruited

80+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

The combination of the Vigil vaccine and atezolizumab was found to be safe for patients with relapsed ovarian cancer, with no dose-limiting toxicities reported in the initial safety assessment involving 3 patients.

Patients receiving the Vigil vaccine first (Vigil-1st) showed a significantly improved median overall survival compared to those starting with atezolizumab (Atezo-1st), with a hazard ratio of 0.33, indicating a potential benefit for further investigation, especially in BRCA wild-type patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Proof of principle study of sequential combination atezolizumab and Vigil in relapsed ovarian cancer. Rocconi, RP., Stevens, EE., Bottsford-Miller, JN., et al.[2022]

Atezolizumab, a PD-L1 inhibitor, was well tolerated in patients with advanced ovarian and uterine cancers, with no new safety concerns and mostly mild treatment-related adverse events.

Preliminary results showed anti-tumor activity in some patients, with long durations of response, suggesting that atezolizumab may be a promising treatment option for these cancers, especially in those with high microsatellite instability.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety, clinical activity and biomarker assessments of atezolizumab from a Phase I study in advanced/recurrent ovarian and uterine cancers. Liu, JF., Gordon, M., Veneris, J., et al.[2019]

A 64-year-old woman with recurrent ovarian cancer, previously unresponsive to standard therapies, showed a near-complete response to the immunotherapy atezolizumab after three cycles, indicating potential efficacy in this patient population.

The patient's tumor exhibited loss of MLH1 and PMS2 proteins, suggesting that identifying specific biomarkers may be crucial for selecting effective treatments for ovarian cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dramatic response to single-agent atezolizumab in a patient with MSI-H serous ovarian cancer. Ak, N., Vatansever, S.[2022]

In a phase II trial involving 104 patients with recurrent ovarian cancer, vismodegib did not significantly improve progression-free survival (PFS) compared to placebo, with median PFS of 7.5 months for vismodegib versus 5.8 months for placebo.

The most common side effects of vismodegib included changes in taste, muscle spasms, and hair loss, with a higher incidence of grade 3/4 adverse events in the vismodegib group (23.1%) compared to placebo (11.5%).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II, randomized, placebo-controlled study of vismodegib as maintenance therapy in patients with ovarian cancer in second or third complete remission. Kaye, SB., Fehrenbacher, L., Holloway, R., et al.[2015]

Erivedge (vismodegib) was approved by the FDA for treating recurrent, locally advanced, or metastatic basal cell carcinoma (BCC) based on a trial showing an overall response rate of 30.3% in metastatic cases and 42.9% in locally advanced cases, with median response durations of 7.6 months for both groups.

The treatment was generally well-tolerated, though common side effects included muscle spasms, alopecia, and fatigue; however, it is important to note that vismodegib is a potent teratogenic agent, indicating significant safety considerations for pregnant patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. Food and Drug Administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma. Axelson, M., Liu, K., Jiang, X., et al.[2022]

In a phase Ib study involving 20 patients with platinum-resistant ovarian cancer, the combination of atezolizumab and bevacizumab demonstrated a safety profile consistent with the individual drugs, with 95% experiencing treatment-related adverse events, but no grade 5 events reported.

The treatment resulted in a 15% overall response rate, with some patients achieving durable responses lasting up to 18.9 months, and a disease control rate of 55%, indicating potential efficacy in managing this challenging cancer type.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Clinical Activity of Atezolizumab Plus Bevacizumab in Patients with Ovarian Cancer: A Phase Ib Study. Moroney, JW., Powderly, J., Lieu, CH., et al.[2021]

In the phase III IMagyn050 trial involving patients with newly diagnosed ovarian cancer, the addition of atezolizumab to standard chemotherapy did not improve progression-free survival (PFS) in patients with BRCA1/2 mutations or homologous recombination deficiency (HRD).

Despite the presence of BRCA1/2 mutations or HRD, most ovarian tumors exhibited low tumor mutation burden (TMB), indicating that genomic instability does not predict enhanced sensitivity to immune checkpoint inhibitors like atezolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of Genomic Landscape on Cancer Immunotherapy for Newly Diagnosed Ovarian Cancer: Biomarker Analyses from the IMagyn050 Randomized Clinical Trial. Landen, CN., Molinero, L., Hamidi, H., et al.[2023]

Vismodegib (Erivedge) is an effective treatment for advanced basal cell carcinoma, targeting the Hedgehog signaling pathway that is often overactive in this type of skin cancer.

Clinical studies have demonstrated that Vismodegib can lead to significant tumor shrinkage and improved outcomes for patients with advanced cases, highlighting its role as a key therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vismodegib (erivedge) for advanced Basal cell carcinoma. Fellner, C.[2023]

Vismodegib is a first-in-class hedgehog pathway inhibitor that effectively blocks the SMO protein, which is crucial for preventing inappropriate activation of the hedgehog signaling pathway linked to cancer.

Clinical trials, including a pivotal Phase II study, have shown that vismodegib is effective in treating advanced basal cell carcinoma with a generally tolerable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vismodegib: a promising drug in the treatment of basal cell carcinomas. Dirix, L., Rutten, A.[2012]

A survey of oncologists and dermato-oncologists across several European countries showed that 95% of respondents in 2018 were aware of the teratogenic risks associated with vismodegib, indicating effective communication of safety information.

The majority of physicians (95% in 2018) reported taking appropriate precautions to minimize the risk of teratogenicity when prescribing vismodegib, demonstrating a strong adherence to safety protocols established by the Erivedge Pregnancy Prevention Program.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vismodegib (ERIVEDGE) pregnancy prevention programme: assessment of risk awareness. Schnetzler, G., Cuberos, M., Bucher, R., et al.[2022]

In a phase III trial involving newly diagnosed stage III/IV ovarian cancer patients, the addition of atezolizumab to standard therapy did not significantly improve overall survival compared to placebo, with a hazard ratio of 0.92 in the intent-to-treat population.

Patient-reported outcomes related to symptoms, functioning, and quality of life showed no significant differences between the atezolizumab and placebo groups, indicating that the treatment did not impose additional burdens on patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overall survival and patient-reported outcome results from the placebo-controlled randomized phase III IMagyn050/GOG 3015/ENGOT-OV39 trial of atezolizumab for newly diagnosed stage III/IV ovarian cancer. Pignata, S., Bookman, M., Sehouli, J., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05538091

Vismodegib Combined With Atezolizumab in Platinum ... This trial will employ the combination of vismodegib and atezolizumab as it has been shown that inhibition of hedgehog signaling in the tumor stroma can reverse ...

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-03173

Vismodegib and Atezolizumab for the Treatment of ... Giving a combination of vismodegib and atezolizumab may work better than either drug alone in treating platinum-resistant ovarian, fallopian tube, or primary ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT05538091?term=AREA%5BInterventionSearch%5D(ERIVEDGE)%20AND%20AREA%5BStudyType%5D(INTERVENTIONAL)&rank=3

Study Details | Vismodegib Combined With Atezolizumab ... The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.

4. withpower.com withpower.com/trial/phase-2-hedgehog-inhibitor-9-2022-1f828

Vismodegib + Atezolizumab for Ovarian Cancer Participants are monitored for safety and effectiveness after treatment, including assessment of objective response rate, progression-free survival, and overall ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10137063/

Immunotherapy for Peritoneal Carcinomatosis - PubMed Central Numerous catumaxomab studies have demonstrated therapeutic efficacy in treating malignant ascites from primary gastric, ovarian, and CRC tumors [77,78]. In a ...

6. centerwatch.com centerwatch.com/clinical-trials/listings/NCT05538091/vismodegib-combined-with-atezolizumab-in-platinum-resistant-ovarian-fallopian-tube-and-primary-peritoneal-cancer

Vismodegib Combined With Atezolizumab in Platinum ... This trial will treat patients with platinum resistant ovarian, fallopian tube or primary peritoneal cancer as defined by a progression free ...

7. roche.com roche.com/media/releases/med-cor-2020-07-13

Roche provides update on Phase III study of Tecentriq in ... Data for the overall survival (OS) co-primary endpoint are currently immature and follow-up will continue until the next planned analysis.