NCT03593915 · REGISTRY CONDITION SEARCH

A Phase 1b/2 Study of Alvocidib Plus Decitabine or Azacitidine in Patients With MDS

Found through the registry condition index, not selected as a treatment recommendation. This discovery collection was restricted to studies with posted results.

Phase: PHASE1, PHASE2
Status at capture: TERMINATED
Registry last update: 2023-11-09

Alvocidib, a cyclin-dependent kinase 9 (CDK 9) inhibitor, in time-sequential therapy demonstrated significant clinical activity in secondary AML patients with prior MDS. Patients with IPSS-R intermediate and above MDS have an increased risk of developing AML and may be treated with the same chemotherapy regimens used in patients with AML. Eight Phase I or II clinical trials have been completed in patients with AML, totaling more than 400 patients with both relapsed/refractory or newly diagnosed AML. Preclinical studies have demonstrated that decitabine exposure increased the expression of NOXA, which is a specific antagonist of the survival factor MCL 1. Pharmacologic downregulation of MCL-1 via CDK 9 inhibition, as well as upregulation of the MCL-1 antagonist, NOXA, following decitabine exposure may result in enhanced antileukemic activity in MCL-1-dependent malignancies.

Open the original ClinicalTrials.gov record → · Download preserved record

What did the study report?

Outcomes, safety and baseline populations are separate source sections. Quality-of-life measures appear under their original outcome titles.

flow

Participant flow

→

baseline

Baseline characteristics

→

outcome · POSTED

Number of Participants With Adverse Events and Serious Adverse Events

→

outcome · POSTED

Tolerability of Alvocidib as Evaluated by Incidence of Dose Limiting Toxicities (DLTs) as Observed in Cycle 1

→

outcome · POSTED

Determination of the Complete Response Rate

→

outcome · POSTED

Improvement in Transfusion Dependence

→

adverse events

Adverse events

→

more info

Limitations, agreements, and source contact

→

Who could take part

eligibility Criteria: Inclusion Criteria: 1. Aged ≥18 years 2. Phase 1b Dose Escalation: Patients with previously untreated MDS and patients with MDS who received fewer than six (6) cycles of previous HMAs. Phase 1b Expansion: Untreated patients with de novo or secondary MDS. Phase 2: Untreated patients with de novo or secondary MDS 3. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score ≤2 at enrollment 4. Provide written informed consent prior to any study-related procedure. (In the event that the patient is re-screened for study participation or a protocol amendment alters the care of an ongoing patient, a new informed consent form must be signed.) 5. Patients with a life expectancy of ≥3 months (90 days) 6. Patients with adequate major organ functions meeting the following criteria on the basis of laboratory data within 4 weeks (28 days) before enrollment (if multiple data are available, most recent data during the period): 1. Serum creatinine: ≤1.8× the upper limit of the normal (ULN) range 2. Total bilirubin: ≤2× the ULN 3. Aspartate transaminase (AST) and alanine transaminase (ALT): ≤3× the ULN 4. Left ventricular ejection fraction (LVEF) \>45% by echocardiogram or multigated acquisition (MUGA) scan 7. Be able to comply with the requirements of the entire study. 8. Patients with Revised International Prognostic Scoring System (IPSS-R) intermediate-, high-, and very high-risk MDS Exclusion Criteria: 1. Presence of concomitant severe cardiovascular disease: 1. Patients who had myocardial infarction within 6 months (180 days) before enrollment 2. Patients with significant diseases at enrollment that may affect study treatment, such as New York Heart Association (NYHA) Functional Class III or IV heart disease, National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade ≥3 arrhythmia, angina pectoris, abnormal electrocardiogram findings, interstitial pneumonia or pulmonary fibrosis 2. Presence of concomitant malignancy requiring chemotherapy or any malignancy (except basal and squamous cell carcinoma of the skin) for which the patient received chemotherapy within 6 months prior to enrollment. NOTE: Diagnosis of any previous or concomitant malignancy is thus not an exclusion criterion. 3. Presence of uncontrolled or uncontrollable infection(s); or ≥Grade 3 infection according to NCI CTCAE v5.0 4. Presence of any psychological, familial, sociological or geographical condition that, in the opinion of the investigator, could potentially hinder compliance with the study protocol and follow-up schedule 5. Patients with a dry tap on bone marrow aspiration before enrollment 6. Patients with concurrent autoimmune disease or a history of chronic or recurrent autoimmune disease, or patients who require long-term systemic steroid therapy greater than the equivalent of 20 mg of prednisone daily (excluding therapy given on an 'as needed' \[PRN\] basis) 7. Patients with other documented malignancies within past year aside from synchronous or metachronous multiple cancers with a disease-free period of ≤5 years (excluding carcinoma in situ, mucosal carcinoma, or other such carcinomas curatively treated with local therapy) 8. Patients with ≥Grade 2 hemorrhage according to NCI CTCAE v5.0 9. Patients who have previously received alvocidib or another cyclin-dependent kinase 9 (CDK9) inhibitor 10. Patients who are pregnant or breastfeeding 11. Female patients of childbearing potential who are sexually active and unwilling to use a medically acceptable method of contraception associated with a low failure rate prior to study entry, for the duration of study participation and for at least 6 months after the last dose of study drug. (Patients will be considered to be of childbearing potential unless surgically sterilized by hysterectomy, or bilateral tubal ligation / salphingectomy, or postmenopausal for at least 2 years.) 12. Male patients with partners of childbearing potential who are unwilling to use condoms in combination with a second effective method of contraception during the trial and for at least 3 months after the last administration of study treatment. 13. Patients who are inappropriate for participation in the study for other reasons in the opinion of the investigator or sub-investigator(s) 14. Patients with a known hypersensitivity to decitabine (those patients enrolled in escalation) or azacitidine or mannitol 15. Patients who have received erythropoietin-stimulating agents (ESAs) within 2 weeks (14 days) prior to Cycle 1/Day 1
healthy Volunteers: false
minimum Age: 18 Years
sex: ALL
std Ages: ADULT
OLDER_ADULT

Treatment arms and interventions

arm Groups

description
* Patients with previously untreated MDS * Patients with MDS who have received \<6 cycles of HMAs (during dose escalation only) * Patients with de novo (cause unknown) or secondary MDS (treatment-related) who are not eligible for intensive induction chemotherapy or stem cell transplant * All French-American-British (FAB) subtypes * Intermediate and above per IPSS-R groups
intervention Names
Combination Product: Alvocidib Plus Decitabine (during dose escalation only) or Azacitidine
label
Ph 1b and 2: MDS
type
EXPERIMENTAL

interventions

arm Group Labels
Ph 1b and 2: MDS
description
PHASE 1b: Decitabine administered as an intravenous (IV) infusion daily for 5 days at a dose of 20 mg/m2 followed on Day 8 by alvocidib as a loading dose over 30 minutes followed by a 4-hour IV infusion (hybrid dosing) Once the maximum dose of alvocidib administered via hybrid dosing has been determined, 2 cohorts of patients will receive azacitidine followed by alvocidib administered as an IV infusion. Azacitidine may be administered as either an IV bolus over 10 to 40 minutes or as a subcutaneous (SC) injection on either a 7 day or 5-2 2 schedule. Regardless of which azacitidine schedule or route of administration is used, alvocidib will be given on Day 10 as a 30-to-60 minute IVI PHASE 2: The Phase 2 study will use the RP2D from the Phase 1b study and follow a Simon 2-stage minimax design using the RP2D of alvocidib administered as a 30-to-60 minute IV infusion determined in the Ph1b study to explore efficacy of alvocidib when administered in sequence after azacitidine.
name
Alvocidib Plus Decitabine (during dose escalation only) or Azacitidine
type
COMBINATION_PRODUCT

Study design

allocation

intervention Model

SINGLE_GROUP

masking Info

masking: NONE

primary Purpose

TREATMENT

Enrollment

count: 20
type: ACTUAL

Registered outcome plans (not posted results)

primary Outcomes

description
Assessment of safety of alvocidib administered in combination with either decitabine (DEC) or azacitidine (AZA) by reporting of adverse events and serious adverse events
measure
Number of Participants With Adverse Events and Serious Adverse Events
time Frame
From the time of first dose to 30 days after the last dose, an average of 33.7 weeks.
description
The DLTs are defined as follows based on the NCI CTCAE v5.0: Must be at least possibly related to Alvocidib; Any Gr 4 nonhematologic toxicity; Gr 3 nonhematologic toxicity that does not resolve to ≤Gr 2 in 48 hours; Gr 3 diarrhea, mucositis, nausea, or vomiting will be considered dose limiting only if resolution to ≤Gr 2 requires \>7 days; and ≥Grade 3 creatinine elevation that does not resolve to \<G2 within 7 days.
measure
Tolerability of Alvocidib as Evaluated by Incidence of Dose Limiting Toxicities (DLTs) as Observed in Cycle 1
time Frame
Cycle 1 (28 days)

secondary Outcomes

description
The calculation for Complete Response Rate is as follows: complete response \[CR\] / complete response with incomplete blood count recovery \[CRi\] / CRmarrow / partial response \[PR\] / hematologic improvement \[HI\]
measure
Determination of the Complete Response Rate
time Frame
From the date of first treatment, every 8 weeks, for the first 6 cycles, for an average of 26 weeks
description
Determine if treatment with alvocidib administered in sequence after DEC or AZA resulted in improvements in transfusion dependence
measure
Improvement in Transfusion Dependence
time Frame
Duration of study treatment up to 6 months

Full study description

brief Summary: Alvocidib, a cyclin-dependent kinase 9 (CDK 9) inhibitor, in time-sequential therapy demonstrated significant clinical activity in secondary AML patients with prior MDS. Patients with IPSS-R intermediate and above MDS have an increased risk of developing AML and may be treated with the same chemotherapy regimens used in patients with AML. Eight Phase I or II clinical trials have been completed in patients with AML, totaling more than 400 patients with both relapsed/refractory or newly diagnosed AML. Preclinical studies have demonstrated that decitabine exposure increased the expression of NOXA, which is a specific antagonist of the survival factor MCL 1. Pharmacologic downregulation of MCL-1 via CDK 9 inhibition, as well as upregulation of the MCL-1 antagonist, NOXA, following decitabine exposure may result in enhanced antileukemic activity in MCL-1-dependent malignancies.
detailed Description: PHASE 1b: Patients will be enrolled in cohorts of 3-6 patients. Escalation of the alvocidib dose will follow a standard 3+3 design with sequential cohorts of 3 patients treated with incrementally higher doses of alvocidib administered in sequence after decitabine (during dose escalation) or azacitidine until a dose-limiting toxicity (DLT) is observed and the MTD is established. Once the MTD or preliminary RP2D of alvocidib administered via hybrid dosing is identified, 2 cohorts of at least 3 patients each will receive azacitadine followed by alvocidib administered as a 30-60 minute IV infusion. Expansion at MTD Once the MTD or preliminary RP2D of alvocidib administered as a 30-to-60 minute IV infusion is determined, up to 25 patients will be enrolled in an Expansion cohort to receive alvocidib following azacitadine to confirm safety, explore potential biomarkers, and evaluate potential signals of alvocidib activity. Once this Expansion cohort is completed, the study will progress to Phase 2 PHASE 2: Phase 2 design is based on the Simon 2-stage minimax design (Simon 1989). * Stage 1: Up to 15 evaluable patients will be enrolled and treated at the RP2D identified in the Phase 1b study. * Stage 2: Ten patients will be enrolled to bring the total enrollment in Phase 2 (including Stage-1 patients) to 25 evaluable patients. Stage-2 patients will also receive the RP2D dose of alvocidib administered by 30-to-60 minute IV infusion identified in the Phase 1b study. If 6 or more responses are observed in 25 patients, the conclusion will be that the combination regimen is worthy of further investigation.

Source references

Source notices and limitations

Discovery and provenance

release id
ctgov-registry-1336d216cbd1bbff780dac70
edge id
nct-edge-0a980dcbd7b17127dd7b
requested nct id
NCT03593915
primary nct id
NCT03593915
source kind
ctgov_condition_query
source url
https://clinicaltrials.gov/api/v2/studies?query.cond=Juvenile+Myelomonocytic+Leukemia&filter.advanced=AREA%5BHasResults%5Dtrue&pageSize=1000&format=json&countTotal=true
source record id
Source null
source file sha256
cddcd4e3a59550bc78924062a298c359d8f811413f73f4a4461963aecf3790d6
payload sha256
37e040587ff338f022ac913c5a6adaaf7ce1e5f004e9627d07e3e348eadd2957
payload
clinical indication matching status
condition_index_match_asserted_by_registry_not_reviewed
end exclusive
true
id
nct-edge-0a980dcbd7b17127dd7b
link basis
returned_by_explicit_condition_and_posted_results_filter_query
nct id
NCT03593915
occurrences
context exact
NCT03593915
end
11
exact text
NCT03593915
start
0
offset unit
unicode_code_points
query cond
Juvenile Myelomonocytic Leukemia
query disease state id
ds-juvenile-myelomonocytic-leukemia
source file
/Users/arunverma/Documents/ChatGPT/Cancer Statistics Website/research-data/2026-09-10/clinicaltrials-condition/round-0000/raw/cond-juvenile-myelomonocytic-leukemia-000.json
source file sha256
cddcd4e3a59550bc78924062a298c359d8f811413f73f4a4461963aecf3790d6
source json pointer
/studies/50/protocolSection/identificationModule/nctId
source kind
ctgov_condition_query
source record id
Source null
source string basis
parsed_JSON_string_unmodified
source string sha256
f406d1f6b02c42a73b77ac15dc3ab62feb222fc1d2866433c2daecf46a52dc6f
source url
https://clinicaltrials.gov/api/v2/studies?query.cond=Juvenile+Myelomonocytic+Leukemia&filter.advanced=AREA%5BHasResults%5Dtrue&pageSize=1000&format=json&countTotal=true

Preserved source evidence · Not medical advice