Description:
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.
Title
- 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
Clinical Trial IDs
- ORG STUDY ID:
210026
- SECONDARY ID:
21-C-0026
- NCT ID:
NCT04941274
Conditions
Interventions
Drug | Synonyms | Arms |
---|
Abemaciclib | | 1/Dose Determination/De-Escalation |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
1/Dose Determination/De-Escalation | Experimental | Abemaciclib (de-escalating dose) | |
2/Dose Expansion: Group 2a | Experimental | 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. | |
2/Dose Expansion: Group 2b | Experimental | Abemaciclib (at optimal dose determined in dose escalation portion of the study) for up to 10 previously untreated participants. | |
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.
- 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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | safety and tolerability of abemaciclib |
Time Frame: | 28 days |
Safety Issue: | |
Description: | The fraction of patients with toxicity noted at each dose level will be reported by grade and type of toxicity identified. |
Secondary Outcome Measures
Measure: | KS response to abemaciclib |
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 |
Safety Issue: | |
Description: | Staging and response to abemaciclib for KS by the evaluation of number, size, nodularity, and color of lesions. |
Measure: | duration of response |
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 |
Safety Issue: | |
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 |
Measure: | Progression free survival |
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 |
Safety Issue: | |
Description: | Duration of time from the start of the treatment until time of disease relapse from PR, disease progression, or death, whichever occurs first |
Details
Phase: | Phase 1/Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Not yet recruiting |
Lead Sponsor: | National Cancer Institute (NCI) |
Trial Keywords
- Angiogenesis
- AIDS
- cyclin-dependent kinase
- KSHV
- Cell Cycle
Last Updated
August 27, 2021