Abemaciclib in Patients With HIV-associated and HIV-negative Kaposi Sarcoma
- Registration Number
- NCT04941274
- Lead Sponsor
- National Cancer Institute (NCI)
- Brief Summary
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.
- Detailed Description
Background:
* Kaposi Sarcoma (KS) is a multicentric angioproliferative tumor, caused by Kaposi sarcoma-associated herpesvirus, that most frequently involves the skin, but may also involve lymph nodes, lungs, bone and gastrointestinal tract. It is most common in people with HIV but may also occur in patients without a diagnosis of HIV. Patients with HIV-associated KS have worse survival than HIV-infected patients without KS.
* As it is a relapsing and remitting condition, patients with KS often require prolonged courses of cytotoxic chemotherapy and improved approaches for refractory and recurrent KS are needed to decrease morbidity among patients with KS.
* Cell cycle dysregulation is one of the hallmarks of cancer and has been developed as a therapeutic target in patients with metastatic breast cancer. Cell cycle is controlled by several proteins, including cyclin D kinases (CDKs), cyclins and retinoblastoma (Rb)-E2F signaling pathway.
* Abemaciclib is an orally available cyclin-dependent kinase (CDK) inhibitor that targets the CDK4 (cyclin D1) and CDK6 (cyclin D3) cell cycle pathways thereby inhibiting retinoblastoma (Rb) protein phosphorylation in early G1.
* KS is an endothelial tumor, and KSHV-infected endothelial cells serve as the best current model for KS as there are no good animal models for this disease. Abemaciclib was found to inhibit proliferation of KSHV-infected and uninfected human umbilical vein endothelial cells (HUVEC) at doses as low as 0.1 microM.
* Published Phase I/II studies demonstrated that abemaciclib led to clinical responses in patients with metastatic breast cancer and other tumor types, such as glioblastoma, colorectal cancer, and melanoma.
* Abemaciclib is a therapy licensed for use in metastatic breast cancer both as monotherapy and in combination with other cancer therapies and the safety and efficacy profiles of this agent are very well known. We hypothesize that abemaciclib will be well-tolerated and participants with KS who have received prior therapies will derive some clinical benefit.
Objectives:
* Phase I: To assess the safety and tolerability of abemaciclib in participants with KS
* Phase II: To assess the overall response rate (ORR) of abemaciclib of all participants and by prior KS therapy (untreated KS vs. previously treated KS), and by Stage T1 KS
Eligibility:
* Age \>=18 years
* Histologically confirmed Kaposi sarcoma (KS)
* KS requiring systemic therapy, with either no prior systemic therapy or history of at least 1 prior line of systemic therapy:
* 3 weeks from last chemotherapy
* 3 weeks from last immunotherapy
* Measurable disease consisting of at least five measurable cutaneous KS lesions with no previous local radiation, surgical or intralesional cytotoxic therapy to these measurable lesions; or, in the absence of measurable cutaneous lesions or less than 5 lesions, evaluable KS by RECIST criteria would be required.
* ECOG Performance Status (PS) \<= 2
* Participant must be willing to give informed consent.
* Participants can be HIV positive or negative.
* Antiretroviral therapy (ART) for HIV+ participants
* Participants receiving other investigational agents will not be eligible.
Design:
* This is a Phase I/II study assessing the safety and efficacy of abemaciclib in participants with previously untreated or treated KS.
* In the Phase I portion of the study, up to 18 KS participants treated with prior therapy will be enrolled in a 3+3 dose de-escalation schema using 2 dose de-escalation levels.
* Following identification of an optimal dose and schedule, an expansion phase (Phase II) will be initiated. The Phase II will involve multiple groups: up to 25 previously untreated or treated KS participants will be enrolled; and, up to 23 KS participants with Stage T1 disease.
* Abemaciclib will be administered as an oral planned starting dose of 200 mg twice daily (in the morning and evening) without regard to meals. Abemaciclib will be given continuously; one cycle equals 28 days.
* Participants will receive therapy until optimal tumor response, unacceptable toxicity, the participant s request to discontinue therapy, or Principal Investigator (PI) decision. Participants with disease progression will have the option of an additional 12 weeks of treatment, if the PI feels that they are deriving clinical benefit.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 86
Not provided
- Participants who have had chemotherapy or immunotherapy within 3 weeks prior to entering the study.
- Participants who received radiotherapy must have completed and fully recovered from the acute effects of radiotherapy. A washout period of at least 14 days is required between end of radiotherapy and enrollment.
- Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > Grade 1) with the exception of alopecia or neuropathy.
- Participants who are receiving any other investigational agents.
- History of severe allergic reactions attributed to compounds of similar chemical or biologic composition to CDK inhibitor.
- Participants receiving any medications or substances that are strong/moderate inhibitors of CYP3A4 are ineligible. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the participant will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the participant is considering a new over-the-counter medicine or herbal product.
- Serious and/or uncontrolled severe intercurrent illness that in the judgement of the investigator would preclude participation in the study.
- No active KSHV-associated multicentric Castleman disease, KSHV-associated inflammatory cytokine syndrome or primary effusion lymphoma.
- Psychiatric illness/social situations that would limit adherence with study requirements.
- Pregnancy
- Prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the regimen are eligible for this trial
- Participants with interstitial lung disease
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description 2/Dose Expansion: Group 2b Abemaciclib Abemaciclib (at optimal dose determined in dose escalation portion of the study) for up to 10 previously untreated participants. 1/Dose Determination/De-Escalation Abemaciclib Abemaciclib (de-escalating dose) 2/Dose Expansion: Group 2a Abemaciclib 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.
- Primary Outcome Measures
Name Time Method safety and tolerability of abemaciclib 28 days The fraction of patients with toxicity noted at each dose level will be reported by grade and type of toxicity identified.
overall response rate every 3 cycles until completion of therapy, then every 3 months for 6 months, then every 6 months for 2 years, then annually for 2 years Percentage of patients with the best overall response of CR or PR to therapy
- Secondary Outcome Measures
Name Time Method KS response to abemaciclib every 3 cycles from cycle 2 until completion of therapy, then every 3 months for 6 months, then every 6 months for 2 years, then annually for 2 years Staging and response to abemaciclib for KS by the evaluation of number, size, nodularity, and color of lesions.
duration of response every 3 cycles until completion of therapy, then every 3 months for 6 months, then every 6 months for 2 years, then annually for 2 years The time criteria are met for CR or PR (whichever is recorded first) until the first date that patient no longer qualifies as a PR
Progression free survival every 3 cycles until completion of therapy, then every 3 months for 6 months, then every 6 months for 2 years, then annually for 2 years Duration of time from the start of the treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first
Trial Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States