Abemaciclib for Kaposi Sarcoma

Overseen By Ramya M Ramaswami, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: National Cancer Institute (NCI)

Must be taking: Antiretrovirals

Must not be taking: CYP3A4 inhibitors

Disqualifiers: Chemotherapy, Immunotherapy, Pregnancy, 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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 5

Duration: Variable (until progression or toxicity)

86 Participants Needed

Trial Summary

What is the purpose of this trial?

Background: Kaposi Sarcoma (KS) is common in people with human immunodeficiency virus (HIV) but can also occur in people who do not have HIV. KS tumors usually involve the skin, but may also involve lymph nodes, lungs, bone, and gastrointestinal tract. Researchers want to see if a drug that is currently used to treat a type of breast cancer can help. Objective: To find a safe dose of abemaciclib to treat KS and to see if it can shrink lesions or tumors. Eligibility: People ages 18 and older with KS. Design: Participants will be screened with some or all of the following: Medical history Physical exam Blood and urine tests Chest x-ray and/or computed tomography scans Lung or gastrointestinal tract exam with an endoscope (a flexible instrument to examine the interior of the organ) Medicine review Heart function tests KS lesion assessment Skin sample from a KS lesion Treatment will be given in 28-day cycles. Participants will take the study drug tablets by mouth everyday. They will keep a medicine diary. They will get the study drug until their cancer gets worse or they have unacceptable side effects. Participants will have a study visit at the beginning of each cycle. At these visits, they will repeat some screening tests. They may have medical photographs taken of body surfaces. They may complete questionnaires about their quality of life. They may give skin and saliva samples. For skin samples, an area of skin will be numbed. A small circle of skin over an area affected by KS will be removed. Participants will have follow-up visits for up to 2 years after treatment ends.

Do I have to stop taking my current medications for the trial?

The trial does not specify if you must stop taking your current medications, but you cannot take strong or moderate inhibitors of CYP3A4. You should discuss your current medications with the trial team to ensure there are no interactions.

Is Abemaciclib generally safe for humans?

Abemaciclib has been studied in various cancers, including breast cancer and non-small cell lung cancer, and is generally considered safe with manageable side effects. Common side effects include diarrhea, infections, and neutropenia (low white blood cell count), with fatigue being a dose-limiting side effect. The maximum tolerated dose is 200 mg every 12 hours. ^{1 2 3 4 5}

How is the drug Abemaciclib different from other treatments for Kaposi Sarcoma?

Abemaciclib is unique because it is a CDK4/6 inhibitor, which means it works by blocking proteins that help cancer cells grow and divide, a mechanism not typically used in treating Kaposi Sarcoma. This approach is different from other treatments that may not specifically target these proteins. ^{6 7 8 9 10}

Research Team

Ramya M Ramaswami, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility Criteria

Adults over 18 with Kaposi Sarcoma (KS), either HIV-positive on effective therapy or HIV-negative, can join. They must have tried at least one KS treatment without success for phase 1, or not received any systemic therapy for phase 2b. Participants need good organ and marrow function, no severe infections, controlled hepatitis if present, and agree to use contraception.

Inclusion Criteria

Your blood counts, liver function, and kidney function need to be within certain ranges. Your heart's pumping function also needs to be above a certain level.

Ability to understand and the willingness to sign a written informed consent document

I've been on ART for 8 weeks without KS improvement in the last 4 weeks.

Exclusion Criteria

Participants who are receiving any other investigational agents

You have had serious allergic reactions to drugs similar to the CDK inhibitor.

I have recovered from side effects of previous cancer treatments, except for hair loss or nerve issues.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive abemaciclib in 28-day cycles until disease progression or unacceptable toxicity

Variable (until progression or toxicity)

1 visit per cycle (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

Every 3 months for 6 months, then every 6 months for 2 years

Optional Extension

Participants with disease progression may receive an additional 12 weeks of treatment if deemed beneficial

12 weeks

Treatment Details

Interventions

• Abemaciclib

Trial Overview The trial is testing Abemaciclib's safety and effectiveness in shrinking KS tumors. It involves taking the drug orally every day in cycles of 28 days until cancer progression or unacceptable side effects occur. The study includes regular health checks, lesion assessments, quality of life questionnaires, and follow-ups for up to two years post-treatment.

Participant Groups

Group I: 2/Dose Expansion: Group 2b Experimental Treatment 1 Intervention

Abemaciclib (at optimal dose determined in dose escalation portion of the study) for up to 10 previously untreated participants.

Group II: 2/Dose Expansion: Group 2a Experimental Treatment 1 Intervention

Abemaciclib (at optimal dose determined in dose escalation portion of the study) for up to 15 participants previously treated with at least 1 line of systemic therapy.

Group III: 1/Dose Determination/De-Escalation Experimental Treatment 1 Intervention

Abemaciclib (de-escalating dose)

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

Approved in United States as Verzenio for:

• Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Approved in European Union as Verzenio for:

• HR+, HER2- advanced or metastatic breast cancer
• HR+, HER2- node-positive early breast cancer

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a phase 1b study involving 50 patients with advanced non-small cell lung cancer (NSCLC), the combination of abemaciclib and pembrolizumab showed significant toxicity, with 80% of patients in cohort A and 76% in cohort B experiencing severe treatment-emergent adverse events.

Despite some antitumor activity, including a disease control rate of 56% in cohort A and 64% in cohort B, the overall risk-benefit profile of this combination therapy does not support further investigation in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib in Combination With Pembrolizumab for Stage IV KRAS-Mutant or Squamous NSCLC: A Phase 1b Study. Pujol, JL., Vansteenkiste, J., Paz-Ares Rodríguez, L., et al.[2022]

Interim results from the MONARCH3 study show that abemaciclib, a CDK4/6 inhibitor, is an effective first-line treatment for advanced ER-positive, HER2-negative breast cancer.

Patients receiving abemaciclib in combination with letrozole experienced significantly improved progression-free survival compared to those receiving a placebo with endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-Line Abemaciclib Effective in ER+ Breast Cancer. [2019]

Abemaciclib, an oral CDK4 and CDK6 inhibitor, was evaluated in a study with 225 patients, showing a maximum tolerated dose of 200 mg every 12 hours and a safety profile that allows for continuous dosing, with fatigue being the most common side effect.

The drug demonstrated significant antitumor activity, particularly in hormone receptor-positive breast cancer, achieving a 31% overall response rate and 61% of patients experiencing either a response or stable disease for at least 6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors. Patnaik, A., Rosen, LS., Tolaney, SM., et al.[2022]

In a phase III trial, abemaciclib combined with endocrine therapy significantly reduced the risk of breast cancer recurrence in patients with hormone receptor positive (HR+), HER2-negative, node-positive early breast cancer, regardless of prior chemotherapy or tumor characteristics.

The combination treatment was generally well-tolerated, with manageable side effects such as diarrhea, infections, and neutropenia, making it a valuable option for high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. Fung, S., Blair, HA.[2023]

Abemaciclib is an oral medication that inhibits cyclin-dependent kinases 4 and 6, specifically approved in the USA for treating advanced or metastatic breast cancer that is hormone receptor-positive and HER2-negative.

It is effective both as a combination therapy with fulvestrant for patients who have progressed after endocrine therapy and as a standalone treatment for those who have also undergone chemotherapy, highlighting its role in advanced cancer management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Abemaciclib: First Global Approval. Kim, ES.[2019]

Vemurafenib is effective for treating BRAF-positive stage IV melanoma, but it can cause a range of skin-related side effects, from mild rashes to more serious conditions like squamous cell carcinoma.

Most dermatologic side effects are manageable and not life-threatening, often requiring only dose adjustments or minor surgical procedures, allowing patients to continue their vemurafenib treatment effectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cutaneous adverse events during vemurafenib therapy. Chandrakumar, SF., Yeung, J.[2018]

In a phase 3 trial involving 675 patients with metastatic melanoma and the BRAF V600E mutation, vemurafenib significantly improved overall survival rates (84% at 6 months) compared to dacarbazine (64%).

Vemurafenib also demonstrated a 63% reduction in the risk of death and a 74% reduction in the risk of disease progression compared to dacarbazine, although it was associated with common adverse effects that led to dose modifications in 38% of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improved survival with vemurafenib in melanoma with BRAF V600E mutation. Chapman, PB., Hauschild, A., Robert, C., et al.[2022]

Vemurafenib is an effective treatment for patients with BRAF (V600E)-positive unresectable or metastatic melanoma, showing a survival benefit in a randomized phase III study.

The drug is generally well tolerated, with common side effects including skin reactions and headache, and research is ongoing to enhance its use and address issues of drug resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Managing Side Effects of Vemurafenib Therapy for Advanced Melanoma. Hagen, B., Trinh, VA.[2022]

Concurrent BRAF-MEK inhibition has shown clinical benefits in patients with advanced melanoma, particularly those with common BRAF V600E/K mutations, but there is emerging evidence for its efficacy in patients with rare BRAF mutations.

Two patients with uncommon BRAF exon 15 mutations experienced positive clinical outcomes and radiological responses to targeted therapy, emphasizing the need for comprehensive testing for all BRAF mutations to identify potential treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Response to targeted therapy in two patients with metastatic melanoma carrying rare BRAF exon 15 mutations: A598_T599insV and V600_K601delinsE. Rogiers, A., Vander Borght, S., Tuand, K., et al.[2018]

BRAF mutations, particularly at the V600 position, are found in up to 50% of melanomas and lead to a constitutively active protein that drives tumor growth, making it a key target for therapy.

Vemurafenib, a selective BRAF inhibitor, showed remarkable efficacy in clinical trials, achieving over 80% tumor regression in patients with BRAF V600E/K mutations, leading to its FDA approval in 2011.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selective BRAF inhibitors make inroads in mutated metastatic melanoma. Tawbi, H.[2019]

References

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

Abemaciclib in Combination With Pembrolizumab for Stage IV KRAS-Mutant or Squamous NSCLC: A Phase 1b Study. [2022]

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

First-Line Abemaciclib Effective in ER+ Breast Cancer. [2019]

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

Efficacy and Safety of Abemaciclib, an Inhibitor of CDK4 and CDK6, for Patients with Breast Cancer, Non-Small Cell Lung Cancer, and Other Solid Tumors. [2022]

4. France pubmed.ncbi.nlm.nih.gov

Abemaciclib: A Review in Early Breast Cancer with a High Risk of Recurrence. [2023]

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

Abemaciclib: First Global Approval. [2019]

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

Cutaneous adverse events during vemurafenib therapy. [2018]

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

Improved survival with vemurafenib in melanoma with BRAF V600E mutation. [2022]

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

Managing Side Effects of Vemurafenib Therapy for Advanced Melanoma. [2022]

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

Response to targeted therapy in two patients with metastatic melanoma carrying rare BRAF exon 15 mutations: A598_T599insV and V600_K601delinsE. [2018]

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

Selective BRAF inhibitors make inroads in mutated metastatic melanoma. [2019]