Sonidegib + Pembrolizumab for Advanced Cancers

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

36 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the drug Sonidegib + Pembrolizumab for Advanced Cancers?

Pembrolizumab, one of the drugs in the treatment, has shown effectiveness in improving survival and response rates in various cancers, such as non-small-cell lung cancer and melanoma, by helping the immune system attack cancer cells more effectively. ^{1 2 3 4 5}

What safety information is available for the combination of Sonidegib and Pembrolizumab in humans?

Pembrolizumab (Keytruda) has been associated with some side effects, including pneumonitis (lung inflammation) in 1%-5% of patients and a rare risk of type 1 diabetes (0.2% of cases). These side effects are related to its role as an immune checkpoint inhibitor, which can sometimes cause the immune system to attack healthy tissues. ^{4 6 7 8 9}

What makes the drug combination of Sonidegib and Pembrolizumab unique for treating advanced cancers?

The combination of Sonidegib and Pembrolizumab is unique because it combines a PD-1 inhibitor, which helps the immune system attack cancer cells, with Sonidegib, a drug that targets a different pathway involved in cancer growth, potentially offering a novel approach for treating advanced cancers. ^{1 3 4 10 11}

What is the purpose of this trial?

This trial tests the best dose of sonidegib combined with pembrolizumab for treating advanced solid tumors. Sonidegib blocks enzymes needed for tumor growth, while pembrolizumab helps the immune system attack cancer. The study focuses on patients with advanced cancers that have spread, aiming to find a more effective treatment than standard options.

Research Team

Mojun Zhu, MD

Principal Investigator

Mayo Clinic in Rochester

Eligibility Criteria

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

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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 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]

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]

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]

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]

References

1. England 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. [2020]

2. United States 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. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. [2017]

4. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. [2017]

5. England 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. [2021]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. [2021]

7. Germany pubmed.ncbi.nlm.nih.gov

Pembrolizumab in advanced osteosarcoma: results of a single-arm, open-label, phase 2 trial. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. [2023]

9. United States pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. [2022]

10. England pubmed.ncbi.nlm.nih.gov

A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus). [2022]

11. Ireland pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. [2022]