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

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, palbociclib (Ibrance) and pembrolizumab (KEYTRUDA), for certain types of soft tissue sarcoma, a form of cancer. The researchers focus on whether administering palbociclib before pembrolizumab alters the tumor to enhance pembrolizumab's effectiveness. Eligible participants include those with advanced sarcoma who have tried at least one other treatment and have no active brain disease. The trial involves taking these medications and undergoing several biopsies to study the cancer's response. This offers eligible individuals a chance to potentially benefit from a new treatment approach. As a Phase 1 trial, the research focuses on understanding how the treatment works in people.

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.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that using palbociclib and pembrolizumab together might be safe and manageable for treating sarcomas, a type of cancer. Although detailed safety information isn't fully available yet, early studies suggest this combination could be promising for patients with advanced sarcomas. Palbociclib alone has demonstrated effectiveness in fighting tumors in patients who have tried other treatments. While this trial remains in the early stages and safety is under close observation, these findings suggest that this combination might be well-tolerated in people. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for sarcoma?

Most treatments for sarcoma involve chemotherapy, surgery, or radiation, but this new combination of palbociclib and pembrolizumab is quite different. Researchers are excited because palbociclib, a CDK4/6 inhibitor, aims to disrupt cancer cell division, potentially making the tumor more susceptible to immune attack. Pembrolizumab, an immunotherapy drug, then helps the body's immune system recognize and destroy cancer cells more effectively. This combination targets the tumor in two ways: by slowing its growth and boosting the immune response, offering a fresh approach that could enhance treatment outcomes for patients with sarcoma.

What evidence suggests that this combination treatment could be effective for soft tissue sarcoma?

Research shows that using palbociclib with pembrolizumab, as studied in this trial, may help treat sarcomas. In previous studies, pembrolizumab alone helped 17.5% of people with advanced sarcoma, particularly undifferentiated pleomorphic sarcoma. Pembrolizumab, which aids the immune system in fighting cancer, and palbociclib, which targets cancer cells, have both been beneficial in treating soft tissue sarcomas. For instance, some patients experienced a 34.4% positive response rate with immune system-boosting drugs. These findings suggest that combining palbociclib and pembrolizumab, as tested in this trial, could be effective for some sarcoma patients. ^{1 4 6 7 8}

Who Is on the Research Team?

John Rieth, MD

Principal Investigator

University of Iowa Hospitals & Clinics

Are You a Good Fit for This Trial?

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

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.

I am 12 years old or older.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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 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 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]

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]

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]

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 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 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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06113809

NCT06113809 | Palbociclib and Pembrolizumab in Sarcoma 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.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12416487/

Immunotherapy and Targeted Therapies in Sarcoma Responses were seen in both cutaneous (ORR, 58%) and noncutaneous (ORR, 67%) disease. The median PFS was 9.6 months (95% CI, 5.3–not reached [NR]) ...

3. withpower.com withpower.com/trial/phase-1-sarcoma-2024-b3aa9

Palbociclib + Pembrolizumab for Sarcoma In a phase II study of pembrolizumab for advanced sarcoma, a 17.5% response rate was observed, particularly in undifferentiated pleomorphic sarcoma and ...

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1567576925000591

Efficacy of immune checkpoint inhibitors in the treatment ... This systematic review and meta-analysis indicate that ICIs, particularly when combined with TKIs, provide substantial therapeutic benefits in treating STS.

5. medicaljournalssweden.se medicaljournalssweden.se/actaoncologica/article/view/43135/50482

View of Real-world data on immune checkpoint inhibitors ... Among the 64 assessable patients, there were three (4.7%) CRs and 19 (29.7%) PRs as best response to ICI, translating into an ORR of 34.4%. Table 2 shows the ...

6. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2024-01021

Palbociclib with Pembrolizumab for the Treatment of ... Palbociclib given with pembrolizumab may be safe, tolerable, and/or effective in treating patients with locally advanced, metastatic or unresectable sarcomas.

7. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.11565

Palbociclib (P) in patients (pts) with soft tissue sarcoma ... Monotherapy P demonstrated anti-tumor activity in heavily pre-treated pts with STS with CDK4 amplification.

8. nature.com nature.com/articles/s41392-023-01661-8

Phase II trial of CDK4/6 inhibitor palbociclib in advanced ... Palbociclib was active in a variety of sarcoma subtypes, selected by CDK4/CDKN2A, and deserves further investigation in the sarcoma context.