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Abemaciclib in Patients With HIV-associated and HIV-negative Kaposi Sarcoma

Primary Purpose

Kaposi Sarcoma

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Abemaciclib
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Kaposi Sarcoma focused on measuring Angiogenesis, AIDS, cyclin-dependent kinase, KSHV, Cell Cycle

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers
  • INCLUSION CRITERIA:
  • Participants must have Kaposi sarcoma confirmed by the Laboratory of Pathology, NCI
  • All participants should have at least five measurable cutaneous KS lesions with no previous local radiation, surgical or intralesional cytotoxic therapy that would prevent response assessment for that lesion.
  • Measurable disease by the criteria proposed by the AIDS Clinical Trials Group Oncology Committee.
  • Participants may be HIV positive or negative.
  • Participants must be able to swallow oral medications
  • For all groups, participants must have adequate organ and marrow function as defined below:

    • Absolute neutrophil count >1,000/mcL
    • Platelets >75,000/mcL
    • Hemoglobin >= 8gm/dL
    • Total bilirubin <= 1.5 upper limit of normal unless the participant is receiving a protease inhibitor known to be associated with increased bilirubin (e.g. atazanavir), in which case total bilirubin <= 7.5 mg/dL with direct fraction <= 0.7
    • AST(SGOT)/ALT(SGPT) <3 X institutional upper limit of normal
    • Creatinine within normal institutional limits OR
    • Creatinine clearance >45 mL/min/1.73 m2 as estimated by either Cockroft-Gault or 24-hour urine collection for participants with creatinine levels above institutional normal
    • Cardiac ejection fraction > 45% by echocardiogram
  • For phase 1: Participants must have received at least 1 prior line of systemic therapy for KS with either plateau in response, progressive disease, or inadequate response to treatment. Previous local therapy or radiation is not considered systemic therapy.
  • For phase 2: Group 2a: Participants must have received at least 1 prior line of systemic therapy for KS with either plateau in response, relapsed disease, progressive disease, or inadequate response to treatment
  • For phase 2: Group 2b: Participants have not received prior systemic therapy for KS. Previous local therapy or radiation is not considered systemic therapy.
  • Age >18 years
  • ECOG performance status <= 2 (Karnofsky >= 60%.
  • Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy are eligible for this trial.
  • Willingness to adhere to ART
  • For all arms of the study, participants must have received ART for 8 weeks prior to enrollment, with no evidence of KS improvement over the most recent 4 weeks
  • For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.
  • Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
  • No uncontrolled severe concurrent bacterial, viral, or fungal infections.
  • Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.
  • The effects of abemaciclib on the developing human fetus are unknown. For this reason and because CDK inhibitors are known to be teratogenic, persons of child-bearing potential and their sexual partners must agree to use adequate pregnancy contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study treatment. Should a person become pregnant or suspect they are pregnant while they or their partner is receiving study drug in this study, the pregnant person should inform their treating physician immediately. Participants with sexual partners of childbearing potential treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study treatment, and 4 months after completion of abemaciclib administration.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • 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.
  • Participants with 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.
  • Participants with psychiatric illness/social situations that would limit adherence with study requirements.
  • Pregnant persons are excluded from this study because abemaciclib is CDK inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the nursing person with abemaciclib, breastfeeding should be discontinued if the nursing person is treated with abemaciclib.
  • Participants with a 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

Sites / Locations

  • National Institutes of Health Clinical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

1/Dose Determination/De-Escalation

2/Dose Expansion: Group 2a

2/Dose Expansion: Group 2b

Arm Description

Abemaciclib (de-escalating dose)

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.

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

Outcomes

Primary Outcome Measures

safety and tolerability of abemaciclib
The fraction of patients with toxicity noted at each dose level will be reported by grade and type of toxicity identified.
overall response rate
Percentage of patients with the best overall response of CR or PR to therapy

Secondary Outcome Measures

KS response to abemaciclib
Staging and response to abemaciclib for KS by the evaluation of number, size, nodularity, and color of lesions.
duration of response
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
Duration of time from the start of the treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first

Full Information

First Posted
June 25, 2021
Last Updated
May 27, 2023
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT04941274
Brief Title
Abemaciclib in Patients With HIV-associated and HIV-negative Kaposi Sarcoma
Official Title
A Phase I/II Study of Abemaciclib in Patients With HIV-associated and HIV-negative Kaposi Sarcoma
Study Type
Interventional

2. Study Status

Record Verification Date
May 25, 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 29, 2021 (Actual)
Primary Completion Date
March 1, 2028 (Anticipated)
Study Completion Date
June 1, 2028 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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 patients with KS who have received prior therapies will derive some clinical benefit. Objectives: -To evaluate the safety and tolerability of abemaciclib in participants with both untreated and previously treated Kaposi sarcoma 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 At least five measurable cutaneous KS lesions with no previous local radiation, surgical or intralesional cytotoxic therapy to these measurable lesions. 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. Up to 25 previously untreated or treated KS participants will be enrolled. 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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Kaposi Sarcoma
Keywords
Angiogenesis, AIDS, cyclin-dependent kinase, KSHV, Cell Cycle

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Sequential Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
43 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
1/Dose Determination/De-Escalation
Arm Type
Experimental
Arm Description
Abemaciclib (de-escalating dose)
Arm Title
2/Dose Expansion: Group 2a
Arm Type
Experimental
Arm Description
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.
Arm Title
2/Dose Expansion: Group 2b
Arm Type
Experimental
Arm Description
Abemaciclib (at optimal dose determined in dose escalation portion of the study) for up to 10 previously untreated participants.
Intervention Type
Drug
Intervention Name(s)
Abemaciclib
Intervention Description
An initial dose of 200 mg twice daily and at an MTD dose will be administered orally every day of each 28-day cycle.
Primary Outcome Measure Information:
Title
safety and tolerability of abemaciclib
Description
The fraction of patients with toxicity noted at each dose level will be reported by grade and type of toxicity identified.
Time Frame
28 days
Title
overall response rate
Description
Percentage of patients with the best overall response of CR or PR to therapy
Time Frame
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
Secondary Outcome Measure Information:
Title
KS response to abemaciclib
Description
Staging and response to abemaciclib for KS by the evaluation of number, size, nodularity, and color of lesions.
Time Frame
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
Title
duration of response
Description
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
Time Frame
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
Title
Progression free survival
Description
Duration of time from the start of the treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first
Time Frame
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

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
INCLUSION CRITERIA: Participants must have Kaposi sarcoma confirmed by the Laboratory of Pathology, NCI All participants should have at least five measurable cutaneous KS lesions with no previous local radiation, surgical or intralesional cytotoxic therapy that would prevent response assessment for that lesion. Measurable disease by the criteria proposed by the AIDS Clinical Trials Group Oncology Committee. Participants may be HIV positive or negative. Participants must be able to swallow oral medications For all groups, participants must have adequate organ and marrow function as defined below: Absolute neutrophil count >1,000/mcL Platelets >75,000/mcL Hemoglobin >= 8gm/dL Total bilirubin <= 1.5 upper limit of normal unless the participant is receiving a protease inhibitor known to be associated with increased bilirubin (e.g. atazanavir), in which case total bilirubin <= 7.5 mg/dL with direct fraction <= 0.7 AST(SGOT)/ALT(SGPT) <3 X institutional upper limit of normal Creatinine within normal institutional limits OR Creatinine clearance >45 mL/min/1.73 m2 as estimated by either Cockroft-Gault or 24-hour urine collection for participants with creatinine levels above institutional normal Cardiac ejection fraction > 45% by echocardiogram For phase 1: Participants must have received at least 1 prior line of systemic therapy for KS with either plateau in response, progressive disease, or inadequate response to treatment. Previous local therapy or radiation is not considered systemic therapy. For phase 2: Group 2a: Participants must have received at least 1 prior line of systemic therapy for KS with either plateau in response, relapsed disease, progressive disease, or inadequate response to treatment For phase 2: Group 2b: Participants have not received prior systemic therapy for KS. Previous local therapy or radiation is not considered systemic therapy. Age >18 years ECOG performance status <= 2 (Karnofsky >= 60%. Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy are eligible for this trial. Willingness to adhere to ART For all arms of the study, participants must have received ART for 8 weeks prior to enrollment, with no evidence of KS improvement over the most recent 4 weeks For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated. Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load. No uncontrolled severe concurrent bacterial, viral, or fungal infections. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better. The effects of abemaciclib on the developing human fetus are unknown. For this reason and because CDK inhibitors are known to be teratogenic, persons of child-bearing potential and their sexual partners must agree to use adequate pregnancy contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study treatment. Should a person become pregnant or suspect they are pregnant while they or their partner is receiving study drug in this study, the pregnant person should inform their treating physician immediately. Participants with sexual partners of childbearing potential treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study treatment, and 4 months after completion of abemaciclib administration. Ability to understand and the willingness to sign a written informed consent document. Exclusion Criteria: 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. Participants with 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. Participants with psychiatric illness/social situations that would limit adherence with study requirements. Pregnant persons are excluded from this study because abemaciclib is CDK inhibitor with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the nursing person with abemaciclib, breastfeeding should be discontinued if the nursing person is treated with abemaciclib. Participants with a 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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Anaida Widell
Phone
(240) 760-6074
Email
anaida.widell@nih.gov
First Name & Middle Initial & Last Name or Official Title & Degree
Ramya M Ramaswami, M.D.
Phone
(240) 506-1088
Email
ramya.ramaswami@nih.gov
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Ramya M Ramaswami, M.D.
Organizational Affiliation
National Cancer Institute (NCI)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
For more information at the NIH Clinical Center contact National Cancer Institute Referral Office
Phone
888-624-1937

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
.All IPD recorded in the medical record will be shared with intramural investigators upon request.
IPD Sharing Time Frame
Clinical data available during the study and indefinitely.
IPD Sharing Access Criteria
Clinical data will be made available via subscription to BTRIS and with the permission of the study PI. @@@@@@Requests for all collected IPD data from clinical trials, conducted under a binding collaborative agreement between NCI/DCTD and a pharmaceutical/biotechnology company, that are not under DSMB monitoring must be in compliance with the terms of the binding collaborative agreement and must be approved by NCI/DCTD and the Pharmaceutical Collaborator (i.e., the NCI ETCTN Director in conjunction with the NCI/DCTD Regulatory Affairs Branch)
Links:
URL
https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2021-C-0026.html
Description
NIH Clinical Center Detailed Web Page

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Abemaciclib in Patients With HIV-associated and HIV-negative Kaposi Sarcoma

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