Myelodysplastic Syndrome/Acute Myeloid LeukemiaPhase 1NCT06454409
Regorafenib in Combination With Venetoclax and Azacitidine for the Treatment of Patients With Relapsed or Refractory Acute Myeloid Leukemia
A Phase 1 study testing Azacitidine, Biospecimen Collection and Bone Marrow Aspiration in people with Myelodysplastic Syndrome/Acute Myeloid Leukemia and Recurrent Acute Myeloid Leukemia, run by City of Hope Medical Center at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Myelodysplastic Syndrome/Acute Myeloid Leukemia, Recurrent Acute Myeloid Leukemia, Recurrent Myelodysplastic Syndrome
- What is being tested?
- Azacitidine, Biospecimen Collection and Bone Marrow Aspiration
- Type of treatment
- Injection or infusion, Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteUnited States
- Study dates
- 25 Apr 2025to 6 Sep 2030
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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)
Who cannot join
- 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
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- 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)
Trial locations and contacts
1 site in 1 country.
United States1 site
City of Hope Medical Center
Duarte, California, 91010
About this study
Official title: A Phase 1b Study of the Multi-Kinase Inhibitor Regorafenib in Combination With the BCL-2 Inhibitor Venetoclax Plus Azacitidine in Patients With Relapsed/Refractory Acute Myeloid Leukemia
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.
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- 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:
- 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.
- 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.
- Conditions
- Myelodysplastic Syndrome/Acute Myeloid Leukemia, Recurrent Acute Myeloid Leukemia, Recurrent Myelodysplastic Syndrome, Refractory Acute Myeloid Leukemia, Refractory Myelodysplastic Syndrome
- Being tested
- Azacitidine, Biospecimen Collection, Bone Marrow Aspiration, Regorafenib, Venetoclax
- Medical subject headings
- GATA2 Deficiency, Leukemia, Myeloid, Acute, Myelodysplastic Syndromes
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AzacitidineDrug
Also called 5 AZC, 5-AC, 5-Azacitidine, 5-Azacytidine
Given IV
Biospecimen CollectionProcedure or surgery
Also called Biological Sample Collection, Biospecimen Collected, Specimen Collection
Undergo blood sample collection
Bone Marrow AspirationProcedure or surgery
Undergo bone marrow aspiration
RegorafenibDrug
Also called BAY 73-4506, Regorafenib Anhydrous
Given PO
VenetoclaxDrug
Also called ABT-0199, ABT-199, ABT199, GDC-0199
Given PO
| Study group | Role | What they receive |
|---|---|---|
| Treatment (regorafenib, venetoclax, azacitidine) | Experimental | Patients receive regorafenib PO QD on days 1-21 of each cycle, venetoclax PO QD on days 1-21 of each cycle, and azacitidine 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. Receives: Drug: Azacitidine; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Drug: Regorafenib; Drug: Venetoclax |
What is being measured
The primary outcome is the main question the study is designed to answer.
Dose-limiting toxicity (DLT)
DLT will be defined as any toxicities classified as at least possibly related to the study treatment, that occur during cycle 1 and will be used for dose escalation/de-escalation/expansion decisions. Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.
Measured: Up to completion of cycle 1 (28 days)
Incidence of adverse events (AEs)
AEs will be graded according to the NCI CTCAE v 5.0 and reported by type, frequency, severity, attribution, time course, and duration.
Measured: Up to 30 days after last dose of study drug
Secondary outcomes (8)
Complete remission (CR) rate
Response will be determined using European LeukemiaNet criteria of Dohner et al. Response rates and Clopper-Pearson binomial confidence interval (CI) will be calculated for the CR (CR/ CR with incomplete hematologic recovery [CRi] / CR with partial hematologic recovery [CRh]) rate. CR rate will also be explored based on number/type of prior therapies.
Measured: Up to 1 year
Overall response rate (ORR)
Response will be determined using European LeukemiaNet criteria of Dohner et al. Response rates and Clopper-Pearson binomial CI will be calculated for the ORR (CR/CRi/CRh/partial response [PR] / stable disease [SD]). ORR rate will also be explored based on number/type of prior therapies.
Measured: Up to 1 year
Minimal residual disease (MRD)
MRD status will be determined by standard of care flow cytometry assay performed locally using a 0.01% blast threshold for positivity. MRD will be reported over the study period using both descriptive statistics and graphical methods.
Measured: Up to 1 year
Time to CR
Time to CR will be defined as the time from first study dose to attainment of CR/ CRi/ CRh. Time to CR will be estimated using the product limit method of Kaplan-Meier.
Measured: At first dose of study drug to up to 1 year
Time to first response
Time to first response will be defined as the time from first study dose to attainment of first documetned CR, CRi, CRh, morphologic leukemia-free state (MLFS) or PR. Time to first response will be estimated using the product limit method of Kaplan-Meier.
Measured: At first dose of study drug to first documented response up to 1 year
Duration of response (DOR)
DOR will be defined as the time interval from the date of first documented response to the date of documented disease relapse or death whichever occurs first. DOR will be estimated using the product limit method of Kaplan-Meier.
Measured: At first response to relapse or death up to 1 year
Overall survival (OS)
OS will be defined as the time interval from the date of first study dose to the date of death from any cause. OS will be estimated using the product limit method of Kaplan-Meier.
Measured: At first dose of study drug to death up to 1 year
Progression-free survival (PFS)
PFS will be defined as the time interval from the date of first study dose to the date of first documented disease relapse/progression or death from any cause, whichever occurs first. PFS will be estimated using the product limit method of Kaplan-Meier.
Measured: At first dose of study drug to relapse, progression, or death up to 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jun 2024
- Study start25 Apr 2025
- Primary completion6 Sep 2030 (estimated)
- Study completion6 Sep 2030 (estimated)
Why it stopped: resources
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Myelodysplastic Syndrome/Acute Myeloid LeukemiaStudies of the same condition, open and under way.
- More trials run by City of Hope Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 20 participants (estimated)
Sponsor and investigators
- Lead sponsor
- City of Hope Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- National Cancer Institute (NCI)
- Responsible party
- Sponsor
- Investigators
- Paul Koller, Principal investigator, City of Hope Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06454409
- Sponsor's protocol ID
- 23713
- Other IDs
- NCI-2024-04611, 23713, P30CA033572
- Status last verified
- Oct 2026
- First submitted
- 6 Jun 2024
- Last updated
- 20 Oct 2026
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No