Trial Title:
Regorafenib in Combination With Venetoclax and Azacitidine for the Treatment of Patients With Relapsed or Refractory Acute Myeloid Leukemia
NCT ID:
NCT06454409
Condition:
Myelodysplastic Syndrome/Acute Myeloid Leukemia
Recurrent Acute Myeloid Leukemia
Recurrent Myelodysplastic Syndrome
Refractory Acute Myeloid Leukemia
Refractory Myelodysplastic Syndrome
Conditions: Official terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Preleukemia
Myelodysplastic Syndromes
Syndrome
Recurrence
Azacitidine
Venetoclax
Study type:
Interventional
Study phase:
Phase 1
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Azacitidine
Description:
Given IV
Arm group label:
Treatment (regorafenib, venetoclax, azacitidine)
Other name:
5 AZC
Other name:
5-AC
Other name:
5-Azacitidine
Other name:
5-Azacytidine
Other name:
5-AZC
Other name:
Azacytidine
Other name:
Azacytidine, 5-
Other name:
Ladakamycin
Other name:
Mylosar
Other name:
U-18496
Other name:
Vidaza
Intervention type:
Procedure
Intervention name:
Biospecimen Collection
Description:
Undergo blood sample collection
Arm group label:
Treatment (regorafenib, venetoclax, azacitidine)
Other name:
Biological Sample Collection
Other name:
Biospecimen Collected
Other name:
Specimen Collection
Intervention type:
Procedure
Intervention name:
Bone Marrow Aspiration
Description:
Undergo bone marrow aspiration
Arm group label:
Treatment (regorafenib, venetoclax, azacitidine)
Intervention type:
Drug
Intervention name:
Regorafenib
Description:
Given PO
Arm group label:
Treatment (regorafenib, venetoclax, azacitidine)
Other name:
BAY 73-4506
Other name:
Regorafenib Anhydrous
Intervention type:
Drug
Intervention name:
Venetoclax
Description:
Given PO
Arm group label:
Treatment (regorafenib, venetoclax, azacitidine)
Other name:
ABT-0199
Other name:
ABT-199
Other name:
ABT199
Other name:
GDC-0199
Other name:
RG7601
Other name:
Venclexta
Other name:
Venclyxto
Summary:
This phase Ib trial tests the safety, side effects, best dose and effectiveness of
regorafenib in combination with venetoclax and azacitidine in treating patients with
acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed)
or that has not responded to previous treatment (refractory). Regorafenib is in a class
of medications called kinase inhibitors. It works by blocking the action of an abnormal
protein that signals cancer cells to multiply. This helps to slow or stop the spread of
cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2)
inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed
for cancer cell survival. Azacitidine is in a class of medications called demethylation
agents. It works by helping the bone marrow to produce normal blood cells and by killing
abnormal cells. Giving regorafenib in combination with venetoclax and azacitidine may be
safe, tolerable and/or effective in treating patients with relapsed or refractory AML.
Detailed description:
PRIMARY OBJECTIVES:
I. Evaluate the safety and tolerability of the multikinase inhibitor regorafenib in
combination with the BCL2 inhibitor/BH3-mimetic venetoclax plus the hypomethylating agent
azacitidine in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML).
II. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of
regorafenib when co- administered with venetoclax and azacitidine.
SECONDARY OBJECTIVES:
I. Evaluate the anti-leukemic activity, as assessed by overall response rate (ORR:
complete remission [CR] + CR with incomplete hematologic recovery [CRi] + CR with partial
hematologic recovery [CRh] + partial remission [PR]) within the first 28 days (cycle 1).
II. Evaluate the anti-leukemic activity, as assessed by complete remission (CR+CRi+CRh),
overall response (ORR: CR+CRi+CRh+PR) and minimal residual disease (MRD)- rate and
duration over the study period.
III. Estimate overall survival (OS), progression-free survival (PFS) and duration of
response (DOR) rate at 6 months and 1 year.
EXPLORATORY OBJECTIVES:
I. Determine biomarkers that may be predictive of regorafenib activity in this
combination.
II. To evaluate expression levels of VEGF, phosphatidylinositol-glycan (PIG), and soluble
(s)VEGFR2 pre and post-treatment.
III. To evaluate changes in angiogenesis and inflammation pre and post treatment by gene
expression.
IV. To characterize gene expression changes, including genes involved in the RAS/MAPK
pathway, by ribonucleic acid (RNA) sequencing pre and post treatment with regorafenib
when co-administered with venetoclax and azacitidine.
V. To evaluate changes in the gene mutation status of leukemic cells before and after
treatment with regorafenib, azacitidine, and venetoclax.
VI. Evaluate changes to phosphorylated (phospho)-ERK after treatment with combination
therapy.
OUTLINE: This is a dose-escalation study of regorafenib in combination with venetoclax
and azacitidine followed by a dose-expansion study.
Patients receive regorafenib orally (PO) once daily (QD) on days 1-21 of each cycle,
venetoclax PO QD on days 1-21 of each cycle, and azacitidine intravenously (IV) over
10-40 minutes on days 1-7 of each cycle. Cycles repeat every 28 days for up to 12 cycles
in the absence of disease progression or unacceptable toxicity. Patients also undergo
bone marrow aspiration during screening and on study as well as blood sample collection
on study.
After completion of study treatment, patients are followed up at 30 days then every 3
months for up to 1 year.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Documented informed consent of the participant and/or legally authorized
representative
- Age: ≥ 18 years
- Eastern Cooperative Oncology Group (ECOG) ≤ 2
- Patients with histologically confirmed AML, according to World Health Organization
(WHO) criteria, with refractory/relapsed (R/R) disease who are ineligible for
therapies known to be effective for treatment of their AML
- Patients with extramedullary disease may be included if they also have marrow
involvement
- Patients with acute promyelocytic leukemia (APL) will not be eligible
- Patients with R/R myelodysplastic syndrome (MDS)/AML, as defined by the presence of
10 - 19% blasts, are also eligible at the discretion of the principal investigator
(PI)
- Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior
anti-cancer therapy
- Ability to swallow pills
- White blood cells (WBC) ≤ 25 x 10^9/L prior to initiation of study therapy.
Cytoreduction with hydroxyurea prior to treatment and/or during cycle 1 may be
required (To be performed within 14 days prior to day 1 of protocol therapy)
- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless has Gilbert's disease)
(To be performed within 14 days prior to day 1 of protocol therapy)
- Aspartate aminotransferase (AST) ≤ 3.0 x ULN (To be performed within 14 days prior
to day 1 of protocol therapy)
- Alanine aminotransferase (ALT) ≤ 3.0 x ULN (To be performed within 14 days prior to
day 1 of protocol therapy)
- Creatinine clearance of ≥ 45 mL/min per 24 hour urine test or the Cockcroft-Gault
formula (To be performed within 14 days prior to day 1 of protocol therapy)
- International normalized ratio (INR) OR Prothrombin (PT) ≤ 1.5 x ULN (To be
performed within 14 days prior to day 1 of protocol therapy)
- Activated partial thromboplastin Time (aPTT) ≤ 1.5 x ULN (To be performed within 14
days prior to day 1 of protocol therapy)
- Corrected QT interval by Fredericia (QTcF) ≤ 480 ms based on Fridericia's formula.
(To be performed within 14 days prior to day 1 of protocol therapy) Note: To be
performed within 28 days prior to day 1 of protocol therapy
- Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required. (To be performed within 14 days prior to day 1 of protocol
therapy)
- Agreement by females and males of childbearing potential to use an effective method
of birth control or abstain from heterosexual activity for the course of the study
through at least 4 months (males) and 7 months (females) after the last dose of
protocol therapy
- Childbearing potential defined as not being surgically sterilized (men and
women) or have not been free from menses for > 1 year (women only)
Exclusion Criteria:
- Hematopoietic stem cell transplant within 100 days prior to day 1 of protocol
therapy
- Chemotherapy, radiation therapy, biological therapy, immunotherapy within 14 days or
five half-lives (whichever is shorter) prior to day 1 of protocol therapy with the
following exceptions:
- Subjects will be allowed to have been on venetoclax and/or azacitidine at
screening and remain on it through treatment start
- Hydroxyurea is allowed prior to treatment and through cycle 1 for control of
rapidly progressing leukemia
- Strong and moderate CYP3A4 inducers and strong CYP3A inhibitors within 7 days prior
to day 1 of protocol therapy
- Foods/supplements that are strong inhibitors or strong or moderate inducers of CYP3A
(such as grapefruit, Seville oranges, starfruit and St. John's wort) within 3 days
prior to initiation of and during study treatment
- Systemic steroid therapy > 10 mg/day (≤ 10mg/day prednisone equivalent ok) or any
other form of immunosuppressive medication within 14 days. Inhaled or topical
steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent,
are permitted. Steroids given for infusion prophylaxis or infusion reactions should
not count towards this maximum
- Must not have received or planning to receive live vaccine while being on study or 4
weeks before and after completion of treatment
- Evidence or history of bleeding diathesis or coagulopathy
- Subjects with thrombotic, embolic, venous, or arterial events, such as
cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis
or pulmonary embolism within 6 months of start of study treatment within 6 months of
informed consent
- Presence of a non-healing wound, non-healing ulcer, or bone fracture
- Major surgical procedure or significant traumatic injury within 28 days before start
of study medication
- Pleural effusion or ascites that causes respiratory compromise ( ≥ National Cancer
Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE] version 5.0
grade 2 dyspnea)
- Patients with blast phase chronic myeloid leukemia (CML)
- Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia
(French-American-British [FAB] class M3-AML)
- Active central nervous system (CNS) disease
- Active graft versus host disease (GVHD)
- Unstable cardiac disease as defined by one of the following:
- Cardiac events such as myocardial infarction (MI) within the past 6 months
- Uncontrolled atrial fibrillation or hypertension
- No measurable disease in the bone marrow
- Active diarrhea
- Gastrointestinal disorder that interferes with oral drug absorption such as
malabsorption syndrome
- History of allergic reactions attributed to compounds of similar chemical or
biologic composition to study agent
- Uncontrolled active infection
- Clinically significant uncontrolled illness
- Diagnosis of Gilbert's disease
- Other active malignancy. Patients 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 investigational regimen are eligible for this
trial
- Females only: Pregnant or breastfeeding
- Any other condition that would, in the investigator's judgment, contraindicate the
patient's participation in the clinical study due to safety concerns with clinical
study procedures
- Prospective participants who, in the opinion of the investigator, may not be able to
comply with all study procedures (including compliance issues related to
feasibility/logistics)
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
City of Hope Medical Center
Address:
City:
Duarte
Zip:
91010
Country:
United States
Contact:
Last name:
Paul Koller
Phone:
626-218-2405
Email:
pkoller@coh.org
Investigator:
Last name:
Paul Koller
Email:
Principal Investigator
Start date:
March 20, 2025
Completion date:
February 17, 2027
Lead sponsor:
Agency:
City of Hope Medical Center
Agency class:
Other
Collaborator:
Agency:
National Cancer Institute (NCI)
Agency class:
NIH
Source:
City of Hope Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06454409
