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Danvatirsen Monotherapy Followed by Combination With Venetoclax in Relapsed/Refractory MDS & AML

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ClinicalTrials.gov Identifier: NCT05986240
Recruitment Status : Recruiting
First Posted : August 14, 2023
Last Update Posted : April 18, 2024
Sponsor:
Collaborators:
M.D. Anderson Cancer Center
Flamingo Therapeutics NV
Information provided by (Responsible Party):
Montefiore Medical Center

Brief Summary:
This is a Phase 1 study investigating the safety and efficacy of Danvatirsen as a monotherapy followed by combination with Venetoclax in patients with relapsed/refractory myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). [(FDA OOPD)]

Condition or disease Intervention/treatment Phase
AML/MDS Acute Myeloid Leukemia Myelodysplastic Syndromes Drug: Danvatirsen Combination Product: Danvatirsen + Venetoclax Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study Investigating the Safety & Efficacy of Danvatirsen as Monotherapy Followed by Combination With Venetoclax in Patients With Relapsed/Refractory MDS & AML
Estimated Study Start Date : May 2024
Estimated Primary Completion Date : October 2025
Estimated Study Completion Date : July 2028


Arm Intervention/treatment
Experimental: Danvatirsen Monotherapy

Patients will be enrolled in cohorts of 3 for the Danvatirsen dose escalation substudy. Based on the DLT of the first cohort of participants, subsequent cohorts will either be administered doses at the next higher dose level, de-escalated to the next lower dose level, or remain the same. Dose escalation discontinuations and MTD will be determined as described in the 'Detailed Study Description.' The total duration of 1 cycle is approximately 4 weeks (28 days). Proposed dose levels and treatment schedule are as follows:

Dose Level 1 (DL1): Danvatirsen Day 1 - Day 28 (1mg/kg loading dose on Cycle 1/Day 1 (C1D1), Cycle 1/Day 3 (C1D3); and Cycle 1/Day 5 (C1D5) followed by weekly 1mg/kg infusion for 3 weeks) Dose Level 2 (DL2): Danvatirsen Day 1 - Day 28 (2mg/kg loading dose on C1D1, C1D3, and C1D5 followed by weekly 2mg/kg infusion for 3 weeks) Dose Level 3 (DL3): Danvatirsen Day 1 - Day 28 (3mg/kg loading dose on C1D1, C1D3, and C1D5 followed by weekly 3mg/kg infusion for 3 weeks)

Drug: Danvatirsen
Danvatirsen (AZD9150) is a selective, high-affinity, antisense oligonucleotide inhibitor of signal transducer and activator of transcription 3 (or STAT3).
Other Name: AZD9150

Experimental: Danvatirsen + Venetoclax Combination Therapy

Patients will be enrolled in cohorts of 3 for the Danvatirsen + Venetoclax dose escalation substudy. Dose escalation administration will be as described in the Danvatirsen monotherapy substudy arm and dose escalation discontinuations and MTD will be determined as described in the 'Detailed Study Description.'

Up to 2 dose levels of Danvatirsen will be evaluated based on data from the Danvatirsen monotherapy arm. Dose 1 will be one level lower than the dose with expected target activity.

Venetoclax: 400 mg (or equivalent) administered as fixed dose daily (except for specific dose modifications described in the protocol) orally for 28 days per cycle. To mitigate risk of tumor lysis syndrome, during Cycle 1 Venetoclax will be dose escalated daily to the goal dose of 400mg daily (100mg on Day 1, 200mg on Day 2 and 400mg on Day 3, and onwards, or adjusted dose ramp-up per Venetoclax label if on concomitant azoles).

The three cycles are approximately 28 days each in duration.

Combination Product: Danvatirsen + Venetoclax

Danvatirsen (AZD9150) is a selective, high-affinity, antisense oligonucleotide inhibitor of signal transducer and activator of transcription 3 (or STAT3).

Venetoclax: Commercially available. Venetoclax is a potent, selective small molecule inhibitor of BCL-2, an anti-apoptotic protein found on some types of cancer cells.

Other Name: Venclexta




Primary Outcome Measures :
  1. Response to Therapy as determined by Overall Response Rate [ Time Frame: From 21 days after initiation of study treatment to within 14 days following treatment discontinuation; up to 14 weeks total ]

    Overall Response Rate (ORR) will be used to assess clinical activity in AML and MDS participants. ORR will be measured as the percentage of participants demonstrating an objective overall response based upon a composite of remission related measures for AML and MDS participants as defined below.

    For AML participants, ORR will be defined as any confirmed Complete Remission (CR) + Complete Remission with Incomplete hematologic recovery (CRi) + Partial Remission (PR).

    or, AML = CR + CRi + PR

    For MDS participants, ORR will be defined as any confirmed Complete Remission (CR) + Complete Remission with Partial Hematologic Recovery (CRh) + Hematologic Response (HR).

    or, MDS = CR + CRh + HR

    Higher percentage is indicative of increased clinical activity of the danvatirsen monotherapy and danvatirsen + venetoclax combination therapies.



Secondary Outcome Measures :
  1. Duration of Response [ Time Frame: Up to 3 years after discontinuation of study treatment; up to 3.5 years total ]
    Duration of response will be measured by the number of days from the date of initial response (CRi or better) to the date of first documented disease progression/relapse or death, whichever occurs first. In the event that neither disease progression/relapse or death is documented prior to study termination, analysis cutoff, or the start of confounding anticancer therapy, this endpoint will be censored at the date of last tumor assessment date. An increased duration of response is indicative of how long a patient will respond to treatment without tumor growth or metastasis

  2. Event-free survival [ Time Frame: Up to 3 years after discontinuation of study treatment; up to 3.5 years total ]
    Event-free survival (EFS) will be measured as the number of days from the date of treatment initiation to the date of documented treatment failure, relapse from complete remission, or death from any cause, whichever occurs first. In the event that none of the above are documented prior to study termination, analysis cutoff, or the start of confounding anticancer therapy, this endpoint will be censored at the date of last tumor assessment date

  3. Overall Survival [ Time Frame: Up to 3 years after discontinuation of study treatment; up to 3.5 years total ]
    Overall Survival (OS) will be measured as the number of days from the date of treatment initiation until the date of death

  4. 30 Day All-cause mortality [ Time Frame: 30 days after initiation of study treatment ]
    Number of participant deaths by all causes

  5. 60 Day All-cause Mortality [ Time Frame: 60 days after initiation of study treatment ]
    Number of participant deaths by all causes



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects must be at least 18 years of age at the time of signing the Informed Consent Form (ICF); must voluntarily sign an ICF; and be able to meet all study requirements
  • Morphologically confirmed diagnosis of AML or MDS in accordance with World Health Organization (WHO) diagnostic criteria
  • Subjects with relapsed/refractory AML who are refractory or relapsed to all conventional therapy and do not have any FDA approved or standard therapeutic options & subjects with intermediated/high/very high IPSS-R MDS who are refractory or relapsed to at least 6 cycles of hypomethylating agent based therapy (azacitidine / decitabine based)
  • WBC must be <25,000 and may be reduced with hydroxyurea to reach this goal prior to study start
  • A post-consent bone marrow biopsy must be performed and tissue collected for correlative analysis for entrance to this trial. Correlative sample collection will not be optional on this study.
  • Subjects must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
  • Recovery to ≤ Grade 1 or baseline for any toxicities considered to be due to prior systemic treatments, excluding alopecia
  • Must have adequate hepatic and renal function as follows:

ALT (SGPT) and/or AST (SGOT) ≤ 3x upper limit of normal (ULN) or ≤ 5x ULN if considered to be leukemia related; Direct bilirubin ≤ 1.5 x ULN or ≤ 3x ULN (in patients with know Gilberts syndrome or if considered to be leukemia related)

  • Serum creatinine clearance ≥ 60 mL/min/1.73 m2 either measured or calculated using standard Cockroft-Gault formula

Exclusion Criteria:

  • Acute Promyelocytic Leukemia
  • Low or very low risk MDS by IPSS-R after failure/progression of first line therapy with hypomethylating agents
  • Active, uncontrolled infection. Patients with infection under active treatment and controlled with antibiotics are eligible. Use of prophylactic anti-microbials per institutional standards is allowed.
  • Active documented central nervous system (CNS) leukemia. Patients with a known history of CNS leukemia will be eligible if they have at least two most recent consecutive LPs showing clearance of CNS disease and no active/progressive symptoms thought to be related to the CNS disease.
  • Concurrent treatment with a non-permitted concomitant medication (as noted in protocol appendix)
  • Concurrent anticancer treatment, major surgery, or the use of any investigational drug within 14 days before the start of trial treatment
  • Other malignancy currently being treated or likely to need treatment in next 6 months with the exception of basal or squamous cell carcinoma of the skin or cervical carcinoma in situ, surgically removed malignancies or malignancies definitively treated with chemotherapy, XRT and/or surgery with no evidence of active malignancy or not anticipated to need treatment in next 6 months or malignancies on maintenance therapy (e.g. tamoxifen for breast cancer) will be allowed after discussion and approval by both MPIs
  • Pregnant or breastfeeding females
  • Known current alcohol or drug abuse
  • Clinically significant cardiovascular disease within the past 6 months (e.g. percutaneous intervention, coronary artery bypass graft, documented NYHA class III/IV cardiac heart failure, unstable angina or MI, poorly controlled atrial or ventricular arrhythmia) as determined by the investigator
  • Any psychiatric condition that would prohibit the understanding or rendering of informed consent
  • Legal incapacity or limited legal capacity to sign consent and/or participate in the trial
  • Any condition deemed by the investigator to make the patient a poor candidate for clinical trial and/or treatment with investigational agents.
  • Previous exposure to the investigational agent (danvatirsen) or to other STAT3 inhibitors

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05986240


Contacts
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Contact: Aditi Shastri, MBBS 718-920-4826 ashastri@montefiore.org

Locations
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United States, New York
Montefiore Medical Center Recruiting
Bronx, New York, United States, 10467
Contact: Aditi Shastri, MBBS    718-920-4826    ashastri@montefiore.org   
United States, Texas
M.D. Anderson Cancer Center, Department of Leukemia Not yet recruiting
Houston, Texas, United States, 77030
Contact: Naval Daver, MD    713-794-4392    ndaver@mdanderson.org   
Sponsors and Collaborators
Montefiore Medical Center
M.D. Anderson Cancer Center
Flamingo Therapeutics NV
Investigators
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Principal Investigator: Aditi Shastri, MBBS Montefiore Medical Center
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Responsible Party: Montefiore Medical Center
ClinicalTrials.gov Identifier: NCT05986240    
Other Study ID Numbers: 2022-14320
R01FD007836-01 ( U.S. FDA Grant/Contract )
First Posted: August 14, 2023    Key Record Dates
Last Update Posted: April 18, 2024
Last Verified: April 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Myelodysplastic Syndromes
Hematologic Diseases
Bone Marrow Diseases
Venetoclax
Antineoplastic Agents