Pembrolizumab + Pemetrexed for Bone Cancer

Overseen By Naveed Wagle, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Saint John's Cancer Institute

Must be taking: Folic acid, Vitamin B12, Dexamethasone

Must not be taking: Immunosuppressants, Corticosteroids

Disqualifiers: Immunodeficiency, Autoimmune disease, HIV, 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: 1

Duration: Up to 2 years or until disease progression

21 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must be able to interrupt non-steroidal anti-inflammatory drugs (NSAIDs) around the time of Pemetrexed administration.

What data supports the effectiveness of the drugs Pembrolizumab and Pemetrexed for bone cancer?

Research shows that Pembrolizumab, when used for lung cancer that has spread to the bones, can significantly improve both lung tumors and bone metastasis. Additionally, Pembrolizumab combined with Pemetrexed has been effective in improving survival rates in lung cancer patients, suggesting potential benefits for bone cancer treatment. ^{1 2 3 4 5}

How is the drug combination of Pembrolizumab and Pemetrexed unique for bone cancer treatment?

The combination of Pembrolizumab and Pemetrexed is unique for bone cancer treatment because Pembrolizumab is an immunotherapy that enhances the body's immune response against cancer cells, and it has shown promise in treating bone metastasis in other cancers like non-small cell lung cancer. This approach is different from traditional chemotherapy as it targets the immune system rather than directly attacking cancer cells. ^{1 5 6 7 8}

What is the purpose of this trial?

Primary Objective: 1. To determine objective response rate (ORR) according to RECIST v1.1 of pembrolizumab and high-dose pemetrexed in the treatment of patients with chordoma until disease progression. The OOR will be investigator assessed. Secondary Objectives: 1. To describe the adverse events associated with administering pembrolizumab and high-dose pemetrexed combination treatment. 2. To determine disease control rate based on imaging and overall survival. 3. To determine median PFS and PFS rates at 6, 9, 12, and 18 months. 4. To evaluate changes in volumetric tumor measurements based on imaging. 5. To determine the effects of combination treatment on quality of life, assessed by the EORTC-QLQ-C30 questionnaire. 6. To assess tumor evolution over time in patients with chordoma based on imaging, and molecular profiling. 7. To assess the pharmacodynamic effects of treatment in blood. Exploratory Objective: 1. To explore the relationship between molecular phenotype and patient response.

Eligibility Criteria

This trial is for patients with chordoma, a type of bone cancer, who have seen their disease progress. Participants should meet certain health standards to be eligible but specific inclusion and exclusion criteria are not listed.

Inclusion Criteria

Evidence of progressive disease within the past six months before study entry, according to RECIST v1.1

I can take folic acid, Vitamin B12, and dexamethasone as scheduled.

Participant has measurable disease, according to RECIST v1.1

Exclusion Criteria

I have an autoimmune disease treated with strong medication in the last 2 years.

I have or had lung inflammation not caused by an infection.

Participant has a known history of human immunodeficiency virus (HIV) infection

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive pembrolizumab 200 mg IV infusion and pemetrexed 900 mg/m2 IV infusion on Day 1 of each 21-day cycle

Up to 2 years or until disease progression

1 visit every 21 days (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Pembrolizumab
• Pemetrexed

Trial Overview The study tests the effectiveness of Pembrolizumab combined with high-dose Pemetrexed in treating chordoma. It aims to measure how well tumors respond, control rate of the disease, overall survival time, progression-free survival at various intervals, tumor size changes over time, quality of life impacts and molecular changes in tumors.

Participant Groups

Group I: Single Arm Experimental Treatment 2 Interventions

Eligible patients will receive pembrolizumab 200 mg IV infusion on Day 1 of each 21-day cycle, and pemetrexed 900 mg/m2 by intravenous (IV) infusion on Day 1 of each 21-day treatment cycle and supportive medications (folic acid, vitamin B12, and dexamethasone).

Who Is Running the Clinical Trial?

Saint John's Cancer Institute

Lead Sponsor

Trials

27

Recruited

6,800+

Chordoma Foundation

Collaborator

Trials

4

Recruited

100+

Findings from Research

Treatment with pembrolizumab, an immunotherapy drug, led to significant improvements in both lung tumors and bone metastases in two patients with advanced non-small cell lung cancer (NSCLC) and impending fractures.

After 3 months of treatment, both patients experienced a complete response, showing remarkable bone healing and reduced lung tumor size, suggesting that pembrolizumab may be an effective systemic therapy even in cases with severe bone complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Complete Response of Bone Metastasis in Non-small Cell Lung Cancer With Pembrolizumab: Two Case Reports. Asano, Y., Yamamoto, N., Hayashi, K., et al.[2021]

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 the phase III KEYNOTE-189 study, pembrolizumab combined with pemetrexed and platinum-based chemotherapy significantly improved overall survival (OS) and progression-free survival (PFS) in patients with untreated metastatic nonsquamous non-small-cell lung cancer, with a hazard ratio of 0.56 for OS and 0.49 for PFS after a median follow-up of 31 months.

The treatment was associated with a high objective response rate (ORR) of 48.3% compared to 19.9% for the placebo group, and among patients who completed 35 cycles of pembrolizumab, the ORR was even higher at 85.7%, indicating strong efficacy with manageable toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Rodríguez-Abreu, D., Powell, SF., Hochmair, MJ., et al.[2022]

In a study of 187 patients with non-small-cell lung cancer (NSCLC) and PD-L1 expression of ≥50%, those with PD-L1 levels of 90%-100% showed significantly better treatment outcomes with pembrolizumab, including a higher overall response rate (60% vs. 32.7%) and longer median progression-free survival (14.5 months vs. 4.1 months).

Patients with higher PD-L1 expression not only had improved response rates but also longer overall survival, indicating that PD-L1 levels can be a critical factor in predicting the efficacy of pembrolizumab as a first-line treatment for NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression. Aguilar, EJ., Ricciuti, B., Gainor, JF., et al.[2023]

Pembrolizumab, an immunotherapy for advanced non-small-cell lung cancer (NSCLC), significantly improves progression-free and overall survival compared to traditional chemotherapy, with fewer side effects, particularly in patients with high PD-L1 expression (≥50%).

In combination with pemetrexed and carboplatin, pembrolizumab also enhances treatment effectiveness and maintains manageable toxicity, leading to a shift in first-line treatment strategies for advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. Reck, M.[2018]

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, when combined with carboplatin and pemetrexed, significantly improves overall and progression-free survival rates in patients with non-small cell lung cancer (NSCLC), demonstrating its efficacy as a treatment option.

This case report highlights a unique instance of immune-mediated sarcoidosis developing in a patient with NSCLC after receiving pembrolizumab, indicating potential immune-related side effects of this therapy that require further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulmonary Sarcoidosis Activation following Neoadjuvant Pembrolizumab plus Chemotherapy Combination Therapy in a Patient with Non-Small Cell Lung Cancer: A Case Report. Fakhri, G., Akel, R., Salem, Z., et al.[2022]

In a real-life study of 121 patients with advanced non-squamous non-small cell lung cancer, the combination of pembrolizumab and chemotherapy resulted in a median progression-free survival of 9 months and overall survival of 20.6 months, demonstrating its efficacy as a first-line treatment.

The treatment was generally well-tolerated, with manageable side effects; however, 17.5% of patients experienced grade 3-4 adverse events, and there were two treatment-related deaths, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29). Renaud, E., Ricordel, C., Corre, R., et al.[2023]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Complete Response of Bone Metastasis in Non-small Cell Lung Cancer With Pembrolizumab: Two Case Reports. [2021]

2. 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]

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

Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. [2022]

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

Outcomes to first-line pembrolizumab in patients with non-small-cell lung cancer and very high PD-L1 expression. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. [2018]

6. Germany pubmed.ncbi.nlm.nih.gov

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

7. Switzerland pubmed.ncbi.nlm.nih.gov

Pulmonary Sarcoidosis Activation following Neoadjuvant Pembrolizumab plus Chemotherapy Combination Therapy in a Patient with Non-Small Cell Lung Cancer: A Case Report. [2022]

8. China pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29). [2023]