Sonidegib + Pembrolizumab for Advanced Cancers

Not currently recruiting at 3 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Mayo Clinic

Must not be taking: Statins, CYP3A4 inhibitors

Disqualifiers: Pregnancy, Neuromuscular disorders, Autoimmune diseases, others

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

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

Compensation: Varies

Number of Visits: 28

Duration: Up to 72 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the combination of two drugs, sonidegib and pembrolizumab, to determine the optimal dose and assess their effectiveness against advanced solid tumors that have spread. Sonidegib (Odomzo) may inhibit tumor growth by blocking certain enzymes, while pembrolizumab (KEYTRUDA) aims to enhance the immune system's ability to attack cancer. The trial targets patients with specific types of advanced cancers, such as non-small cell lung cancer or melanoma, who have not responded to previous treatments. Participants must have a solid tumor that has spread and have tried other treatments without success. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this combination therapy.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications before starting treatment. If you are on drugs that cause muscle damage (like some statins) or affect liver enzymes (CYP3A4/5 inhibitors or inducers), you need to stop them at least 2 to 4 weeks before starting the trial. If you need a medication to control cholesterol, pravastatin may be used with caution.

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

Research has shown that sonidegib and pembrolizumab are generally well-tolerated by patients with advanced cancers. However, one study found serious side effects, including high blood sugar, tiredness, upset stomach, and stomach pain. These are considered serious side effects.

Pembrolizumab is already approved for other uses, indicating its safety for those conditions. Researchers are still studying sonidegib in combination with pembrolizumab to determine the safest dose and assess its effectiveness. This research focuses on safety, so any side effects receive close monitoring. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of sonidegib and pembrolizumab for advanced cancers because these drugs offer a unique approach compared to the standard treatments. Pembrolizumab is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells more effectively. Sonidegib is a Hedgehog pathway inhibitor, which can interfere with cancer cell growth and survival. Together, they target cancer from two angles, potentially enhancing the overall anti-cancer effect and overcoming resistance that might occur with existing therapies. This dual-action strategy could offer new hope for patients who have not responded well to current treatment options.

What evidence suggests that sonidegib and pembrolizumab might be effective for advanced solid tumors?

Research shows that combining sonidegib and pembrolizumab, as studied in this trial, may help treat advanced solid tumors. Sonidegib blocks certain proteins that tumor cells need to grow. Studies have found it effective in treating advanced basal cell carcinoma, with some patients experiencing significant tumor shrinkage. Pembrolizumab, a type of immunotherapy, helps the body's immune system fight cancer cells. It has successfully treated various cancers by enhancing the body's ability to prevent tumor spread. Together, these drugs might offer a stronger treatment option for advanced cancers. ^{1 2 5 6 7}

Who Is on the Research Team?

Mojun Zhu, MD

Principal Investigator

Mayo Clinic in Rochester

Are You a Good Fit for This Trial?

Adults with advanced solid tumors, including various cancers like melanoma and lung cancer, who have tried other treatments without success. They must be in good physical condition (ECOG 0 or 1), have measurable disease, and agree to use two forms of contraception if of childbearing potential. Not eligible if pregnant, nursing, expected to live less than three months, or unable to take the study drug due to certain health conditions.

Inclusion Criteria

My cancer has returned or spread and is confirmed by tests.

Women who can have children must have a negative pregnancy test within 7 days before joining the study.

I am fully active or restricted in physically strenuous activity but can do light work.

Exclusion Criteria

I have an autoimmune disease needing regular immune system medications.

I had a severe reaction to previous immunotherapy that needed steroids or stopped treatment.

I have not had major surgery in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Determine the maximum tolerated dose (MTD) of sonidegib in combination with pembrolizumab

21 days

3 visits (in-person)

Treatment

Participants receive sonidegib orally once daily on days 1-8 and pembrolizumab intravenously on day 8, repeating every 21 days for up to 24 cycles

Up to 72 weeks

24 cycles (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Sonidegib

Trial Overview The trial is testing the combination of Sonidegib and Pembrolizumab for treating advanced solid tumors. It aims to find the best dose of Sonidegib that works well with Pembrolizumab—an antibody therapy—to potentially stop tumor growth by blocking enzymes needed for cell growth while helping the immune system attack cancer.

How Is the Trial Designed?

Group I: Treatment (sonidegib, pembrolizumab) Experimental Treatment 2 Interventions

Patients receive sonidegib PO QD on days 1-8, and pembrolizumab IV over 30 minutes on day 8. Treatment repeats every 21 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Mayo Clinic

Lead Sponsor

Trials

3,427

Recruited

3,221,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In the KEYNOTE-189 study involving 616 patients with metastatic non-squamous non-small-cell lung cancer, the combination of pembrolizumab and pemetrexed-platinum significantly maintained quality of life (GHS/QOL) scores compared to placebo, with a notable improvement at week 21.

Patients receiving pembrolizumab also experienced a longer median time to deterioration in symptoms like cough and chest pain, although this result was not statistically significant, indicating potential benefits in symptom management with this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patient-reported outcomes following pembrolizumab or placebo plus pemetrexed and platinum in patients with previously untreated, metastatic, non-squamous non-small-cell lung cancer (KEYNOTE-189): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Garassino, MC., Gadgeel, S., Esteban, E., et al.[2020]

Pembrolizumab (P) can be safely combined with various chemotherapy agents, including gemcitabine and liposomal doxorubicin, in patients with advanced solid tumors, as shown in a phase Ib trial involving 49 patients.

The combination treatment resulted in eight partial responses across different tumor types, indicating potential efficacy, but further studies are needed to confirm if the response duration is better than chemotherapy or immunotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus). Weiss, GJ., Waypa, J., Blaydorn, L., et al.[2022]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

In a phase 2 trial involving 12 patients with advanced osteosarcoma, pembrolizumab showed no clinical benefit at 18 weeks, with all patients experiencing disease progression and a median overall survival of only 6.6 months.

Despite the lack of significant antitumor activity, pembrolizumab was well-tolerated, with no treatment-related deaths or severe adverse events, suggesting it may be safe for use in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in advanced osteosarcoma: results of a single-arm, open-label, phase 2 trial. Boye, K., Longhi, A., Guren, T., et al.[2022]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., et al.[2022]

In a long-term study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab with pemetrexed-carboplatin significantly improved the objective response rate (58% vs. 33%) and progression-free survival (24.5 months vs. 9.9 months) compared to chemotherapy alone.

Patients who completed 2 years of pembrolizumab treatment had a remarkable 92% survival rate at the data cutoff, indicating a durable clinical benefit, while the safety profile remained manageable with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. Awad, MM., Gadgeel, SM., Borghaei, H., et al.[2021]

In the KEYNOTE-659 study, the combination of pembrolizumab with S-1 plus oxaliplatin (SOX) demonstrated a high objective response rate (ORR) of 72.2% in Japanese patients with advanced gastric/gastroesophageal junction cancer, indicating strong efficacy as a first-line treatment.

The treatment was associated with a manageable safety profile, with 57.4% of patients experiencing grade ≥3 treatment-related adverse events, the most common being decreased platelet and neutrophil counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of pembrolizumab in combination with S-1 plus oxaliplatin as a first-line treatment in patients with advanced gastric/gastroesophageal junction cancer: Cohort 1 data from the KEYNOTE-659 phase IIb study. Kawazoe, A., Yamaguchi, K., Yasui, H., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04007744

Sonidegib and Pembrolizumab in Treating Patients With ... This phase I trial studies the best dose of sonidegib when given together with pembrolizumab and to see how well they work in treating patients with solid ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7318253/

Long‐term efficacy and safety of sonidegib in patients with ... Long‐term efficacy and safety of sonidegib in patients with advanced basal cell carcinoma: 42‐month analysis of the phase II randomized, double‐blind BOLT study.

3. asco.org asco.org/abstracts-presentations/ABSTRACT409462

A phase I trial of sequential dosing of sonidegib and ... Grade 3 and above treatment-related AEs across all patients were hyperglycemia, fatigue, dyspepsia, abdominal pain. The mature efficacy data will be reported at ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8395379/

Immunotherapy for Non-melanoma Skin Cancer - PMC At 39 months of follow-up, updated trial results reported an ORR of 60.3% and 48.5% for locally advanced and metastatic BCC, respectively [24].

5. everyone.org everyone.org/explore/compare?id1=25&id2=35

Odomzo (sonidegib) vs Keytruda (pembrolizumab) The efficacy of Odomzo was assessed in a double-blind study where participants treated with Odomzo showed a higher objective response rate compared to those who ...

6. centerwatch.com centerwatch.com/clinical-trials/listings/NCT04007744/sonidegib-and-pembrolizumab-in-treating-patients-with-advanced-solid-tumors

Sonidegib and Pembrolizumab in Treating Patients with ... Sonidegib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, ...

7. connect.careboxhealth.com connect.careboxhealth.com/en-US/trial/listing/108145

Study of Pembrolizumab (MK-3475) in Participants With ... A Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers in Subjects With Advanced Solid Tumors (KEYNOTE 158). Estimated trial completion ...