Palbociclib + Pembrolizumab for Sarcoma

Overseen By John Rieth, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: John Rieth

Must not be taking: Anti-cancer therapy

Disqualifiers: CNS disease, Severe hepatic impairment, 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: 4

8 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single-arm open-label window of opportunity clinical study assessing the impact of pre-treatment with palbociclib.

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 cannot use any other anti-cancer therapy or radiation therapy on the target lesion while participating in the trial.

What data supports the effectiveness of the drug combination Palbociclib and Pembrolizumab for treating sarcoma?

Research shows that pembrolizumab, one of the drugs in the combination, has shown effectiveness in treating certain types of sarcoma, with a 17.5% response rate in a study of advanced sarcoma patients. Additionally, pembrolizumab has been effective in other cancers, like Kaposi sarcoma, suggesting its potential benefit in sarcoma treatment. ^{1 2 3 4 5}

Is the combination of Palbociclib and Pembrolizumab safe for humans?

Pembrolizumab, also known as KEYTRUDA, has been studied for safety in various conditions, including melanoma and sarcoma. Common side effects include fatigue, cough, nausea, and rash, while more serious immune-related side effects can affect the lungs, liver, and thyroid. These studies suggest that while pembrolizumab can have side effects, it is generally considered safe for use in humans. ^{2 3 6 7 8}

What makes the drug combination of Palbociclib and Pembrolizumab unique for treating sarcoma?

This drug combination is unique because it combines Palbociclib, a targeted therapy that inhibits cancer cell growth, with Pembrolizumab, an immunotherapy that helps the immune system attack cancer cells. This approach is novel for sarcoma, a condition with limited treatment options, and aims to enhance the effectiveness of treatment by using two different mechanisms. ^{1 2 3 9 10}

Research Team

John Rieth, MD

Principal Investigator

University of Iowa Hospitals & Clinics

Eligibility Criteria

This trial is for males and females aged 12 or older with advanced, unresectable pleomorphic sarcoma who have tried at least one therapy. They must understand the study and agree to participate, have a decent performance status (ECOG ≤2), no active brain metastases, and not be pregnant or breastfeeding. Participants need proper organ function and can't join if they've had certain heart issues recently or used specific drugs within 4 weeks.

Inclusion Criteria

You are either 18 or older, or have the capacity to understand and voluntarily agree to participate in the study if you are under 18.

I have advanced sarcoma, it's gotten worse after treatment, and pembrolizumab is my next treatment option.

I have treated brain metastasis with no current progression and am not on dexamethasone.

Exclusion Criteria

Serum bilirubin > 1.5x ULN

You have other serious and uncontrolled medical conditions that would prevent you from participating in the study, according to the doctor's opinion.

I have never had lung inflammation caused by medication.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Pre-treatment Biopsy

Pre-treatment ultrasound guided biopsy to establish immunological baseline of the tumor microenvironment

1 day

1 visit (in-person)

Palbociclib Treatment

Participants receive palbociclib for 2 weeks

2 weeks

1 visit (in-person) for biopsy

Pembrolizumab Treatment

Pembrolizumab is started the same day as the second biopsy, with 2 doses administered

4 weeks

2 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

8 weeks

Long-term Follow-up

Progression free survival assessed up to two years following completion of treatment

Up to 2 years

Treatment Details

Interventions

• Palbociclib
• Pembrolizumab

Trial Overview The trial tests Palbociclib in combination with Pembrolizumab on patients with undifferentiated pleomorphic sarcoma. It's an open-label study where all participants receive the same treatment without a comparison group, focusing on the effects of pre-treatment before standard care.

Participant Groups

Group I: Combination of Palbociclib with Pembrolizumab Experimental Treatment 2 Interventions

Palbociclib given for 2 weeks following a pre-treatment ultrasound guided biopsy used to establish an immunological baseline of the tumor microenvironment. After the conclusion of palbociclib therapy, a post-treatment biopsy will be performed to assess the impact of palbociclib on the tumor microenvironment; pembrolizumab will be started the same day as the second biopsy. After 2 doses of pembrolizumab, a third (optional) biopsy could be performed.

Palbociclib is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Ibrance for:

• HR-positive, HER2-negative advanced or metastatic breast cancer

Approved in European Union as Ibrance for:

• HR-positive, HER2-negative locally advanced or metastatic breast cancer

Approved in Canada as Ibrance for:

• HR-positive, HER2-negative advanced or metastatic breast cancer

Approved in Japan as Ibrance for:

• HR-positive, HER2-negative advanced or recurrent breast cancer

Who Is Running the Clinical Trial?

John Rieth

Lead Sponsor

Trials

4

Recruited

70+

Mohammed Milhem

Lead Sponsor

Trials

9

Recruited

240+

Findings from Research

Pembrolizumab demonstrated antitumor activity in patients with classic and endemic Kaposi sarcoma, indicating its potential as a treatment option for this type of cancer.

The findings suggest that pembrolizumab, an immune checkpoint inhibitor, may effectively enhance the immune response against Kaposi sarcoma tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Is Safe and Effective in Kaposi Sarcoma. [2022]

In a phase II study of pembrolizumab for advanced sarcoma, a 17.5% response rate was observed, particularly in undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma, indicating its potential efficacy in these subtypes.

Higher densities of activated T cells and tumor-associated macrophages expressing PD-L1 in pre-treatment biopsies were associated with better responses to pembrolizumab, suggesting that specific immune features may predict treatment outcomes and progression-free survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab. Keung, EZ., Burgess, M., Salazar, R., et al.[2021]

In a phase 2 study involving 86 patients with advanced soft-tissue or bone sarcoma, pembrolizumab demonstrated some efficacy, particularly in undifferentiated pleomorphic sarcoma (40% response rate) and dedifferentiated liposarcoma (20% response rate), although the overall response rate did not meet the primary endpoint.

The treatment was associated with some serious adverse events, including immune-related conditions like adrenal insufficiency and pneumonitis, highlighting the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Tawbi, HA., Burgess, M., Bolejack, V., 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]

In a case study of two patients with advanced myxofibrosarcoma, the combination of regionally administered melphalan and pembrolizumab led to significant treatment responses, including one complete response lasting 2 years and another partial response lasting 6 months.

Post-treatment biopsies showed immune infiltration into the tumors, suggesting that this combination therapy may enhance the immune response against the cancer, prompting further investigation in a clinical trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Case Report: Response to Regional Melphalan via Limb Infusion and Systemic PD1 Blockade in Recurrent Myxofibrosarcoma: A Report of 2 Cases. Bartlett, EK., D'Angelo, SP., Kelly, CM., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

In a study of 655 patients with advanced melanoma, pembrolizumab showed a 5-year overall survival rate of 34%, with even better outcomes (41%) for treatment-naive patients, indicating its long-term efficacy.

The treatment was generally well-tolerated, with 86% of patients experiencing treatment-related adverse events, but only 7.8% discontinued due to these effects, suggesting a manageable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. Hamid, O., Robert, C., Daud, A., et al.[2023]

In a study of 38 patients with soft tissue sarcoma treated with pembrolizumab, the overall objective response rate was 19.4%, with higher efficacy observed in first-line treatment (42.9%) compared to later lines of therapy.

The median progression-free survival was 2.9 months and overall survival was 12.0 months, indicating limited effectiveness in real-world settings, particularly for certain sarcoma subtypes, and highlighting the potential increased risk of severe adverse events when combined with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with pembrolizumab in patients with advanced soft tissue sarcoma. Liu, J., Fan, Z., Bai, C., et al.[2022]

In a phase 2 study involving 98 patients with rare and ultra-rare sarcomas, pembrolizumab showed an objective response rate of 6.2% at week 12, indicating some activity in these difficult-to-treat cancers.

The treatment was associated with manageable toxicity, with the most common severe adverse events being anemia and liver enzyme increases, and no deaths were linked to the drug itself, suggesting it may be a safe option for selected sarcoma histotypes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial. Blay, JY., Chevret, S., Le Cesne, A., et al.[2023]

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]

References

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

Pembrolizumab Is Safe and Effective in Kaposi Sarcoma. [2022]

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

Correlative Analyses of the SARC028 Trial Reveal an Association Between Sarcoma-Associated Immune Infiltrate and Response to Pembrolizumab. [2021]

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

Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. [2022]

4. 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]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Case Report: Response to Regional Melphalan via Limb Infusion and Systemic PD1 Blockade in Recurrent Myxofibrosarcoma: A Report of 2 Cases. [2022]

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

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Five-year survival outcomes for patients with advanced melanoma treated with pembrolizumab in KEYNOTE-001. [2023]

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

Real-world experience with pembrolizumab in patients with advanced soft tissue sarcoma. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with rare and ultra-rare sarcomas (AcSé Pembrolizumab): analysis of a subgroup from a non-randomised, open-label, phase 2, basket trial. [2023]

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

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