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Leukemia, Myeloid, AcutePhase 1NCT02670044

A Study of Venetoclax in Combination With Cobimetinib and Venetoclax in Combination With Idasanutlin in Patients With Relapsed or Refractory Acute Myeloid Leukemia Who Are Not Eligible for Cytotoxic Therapy

A Phase 1 study testing Cobimetinib, Idasanutlin and Venetoclax in people with Leukemia, Myeloid, Acute, run by Hoffmann-La Roche at 17 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The primary objective for this study is to assess the safety and tolerability as well as preliminary efficacy of venetoclax in combination with cobimetinib, and venetoclax in combination with idasanutlin in patients with relapsed or refractory acute myeloid leukemia (R/R) AML who are not eligible for cytotoxic therapy. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Leukemia, Myeloid, Acute
What is being tested?
Cobimetinib, Idasanutlin and Venetoclax
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
88 participants
Where
17 sitesin 4 countries
Study dates
9 Mar 2016to 10 Dec 2020
Phase
Phase 1
Are there results?
None posted in the registry

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

  • Histological confirmation of relapsed or refractory AML after prior anti-leukemic therapy by WHO classification
  • Ineligible for cytotoxic therapy defined by the following:
  • Age (>/=) 75 years or b. age 18- 74 years with at least one of the following comorbidities: i. Eastern Cooperative Oncology Group (ECOG) Performance Status of 2 or 3 ii. Cardiac history of congestive heart failure requiring treatment or ejection fraction (</=) 50% or chronic stable angina iii. Diffusing capacity of the lungs for carbon monoxide (</=) 65% or forced expiratory volume in the first second of expiration (</=) 65% iv. Creatinine clearance (>/=) 30 mL/min to< 45 mL/min v. any other comorbidity that the physician judges to be incompatible with intensive chemotherapy must be reviewed and approved by the Medical Monitor before screening and study enrollment.
  • Life expectancy of at least 12 weeks
  • Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2
  • Adequate liver and renal function

Who cannot join

  • Patients with acute promyelocytic leukemia (French-American-British [FAB] class M3 AML)
  • Known active central nervous system (CNS) involvement with AML at study entry
  • ECOG Performance Status (>/=) 3 in patients who are (>/=) 75 years old or ECOG Performance Status of 4, regardless of age
  • Prior exposure to Bcl-2 inhibitors, murine double minute 2 (MDM2) antagonists or prior exposure to experimental treatment targeting Raf, mitogen-activated protein kinase (MEK), or the mitogen-activated protein kinase (MAPK) RAS/RAF/MEK/ERK MAPK pathway
  • Positive for hepatitis C virus (HCV), hepatitis B surface antigen (HBsAg) and known history of HIV, malignancy, active infection and cardiovascular diseases (CVs)
  • Received strong cytochrome (CYP) 3A inhibitors, moderate CYP3A inhibitors, strong CYP3A inducers and moderate CYP3A inducers within 7 days prior to initiation of study treatment
Show all 16Show fewer
  • History of symptomatic Clostridium difficile infection within 1 month prior to dosing
  • Additional arm specific exclusion criteria:
  • Dose Escalation Arm A (Venetoclax and Cobimetinib):
  • History or evidence of retinal pathology on ophthalmologic examination that is considered a risk factor for neurosensory retinal detachment/central serous chorioretinopathy (CSCR), retinal vein occlusion (RVO), or neovascular macular degeneration
  • Left ventricular ejection fraction (LVEF) below institutional lower limit of normal (LLN) or below 50%, whichever is lower
  • Arm B (Venetoclax and Idasanutlin):
  • Received the following within 7 days prior to the initiation of study treatment: Strong CYP2C8 inhibitors or CYP2C8 substrates, OATP1B1/3 substrates
  • Received the following within 14 days prior to the initiation of study treatment: Strong CYP2C8 inducers
  • History of liver cirrhosis by radiologic, clinical or laboratory data, or biopsy despite normal liver function tests
  • Received treatment with oral or parenteral anticoagulants/anti-platelet agents within 7 days prior to initiation of study treatment.

Trial locations and contacts

17 sites in 4 countries.

17 sites in 4 countries

United States8 sites

  • University of Colorado

    Aurora, Colorado, 80045-2517

  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

  • MD Anderson Cancer Center

    Houston, Texas, 77030

  • USC Norris Cancer Center

    Los Angeles, California, 90033

  • Weill Cornell Medical College

    New York, New York, 10065

  • UC Davis; Comprehensive Cancer Center

    Sacramento, California, 95817

  • Univ of Calif, San Francisco

    San Francisco, California, 94143

  • Wake Forest Baptist Medical Center

    Winston-Salem, North Carolina, 27157

Other trials in United States

Canada3 sites

  • University of Alberta Hospital

    Edmonton, Alberta, T6G 1Z1

  • Jewish General Hospital

    Montreal, Quebec, H3T 1E2

  • Princess Margaret Cancer Center

    Toronto, Ontario, M5G 1Z5

Other trials in Canada

France3 sites

  • Hopital Avicenne, Paris

    Bobigny, 93009

  • Institut Paoli Calmettes

    Marseille, 13009

  • CHU de Bordeaux

    Pessac, 33600

Other trials in France

Italy3 sites

  • University of Bologna

    Bologna, Emilia-Romagna, 40126

  • Presidio san salvatore muraglia

    Pesaro, Emilia-Romagna, 61122

  • Universita di Roma

    Roma, Emilia-Romagna, 100

Other trials in Italy

About this study

Official title: A Phase IB Multi-Arm Study With Venetoclax in Combination With Cobimetinib and Venetoclax in Combination With Idasanutlin in Patients With Relapsed or Refractory Acute Myeloid Leukemia Who Are Not Eligible for Cytotoxic Therapy

The primary objective for this study is to assess the safety and tolerability as well as preliminary efficacy of venetoclax in combination with cobimetinib, and venetoclax in combination with idasanutlin in patients with relapsed or refractory acute myeloid leukemia (R/R) AML who are not eligible for cytotoxic therapy.

Being tested
Cobimetinib, Idasanutlin, Venetoclax
Medical subject headings
Leukemia, Myeloid, Acute

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • CobimetinibDrug

    Cobimetinib will be administered orally as per schedule in Arm description.

  • IdasanutlinDrug

    Idasanutlin will be administered orally as per schedule in Arm description.

  • VenetoclaxDrug

    Venetoclax will be administered orally as per schedule in Arm description.

Study groups in NCT02670044
Study groupRoleWhat they receive
Dose Escalation: Arm A (Venetoclax 400mg + Cobi 40mg)ExperimentalParticipants received Venetoclax 400mg daily on Days 1-28 of each 28 day treatment cycle and Cobimetinib 40mg daily on Days 1-21 of each 28-day treatment cycle.
Receives: Drug: Cobimetinib; Drug: Venetoclax
Dose Escalation: Arm A (Venetoclax 600mg + Cobi 40mg)ExperimentalParticipants received Venetoclax 600mg daily on Days 1-28 of each 28 day treatment cycle and Cobimetinib 40mg daily on Days 1-21 of each 28-day treatment cycle.
Receives: Drug: Cobimetinib; Drug: Venetoclax
Dose Escalation: Arm A (Venetoclax 800mg + Cobi 40mg)ExperimentalParticipants received Venetoclax 800mg daily on Days 1-28 of each 28 day treatment cycle and Cobimetinib 40mg daily on Days 1-21 of each 28-day treatment cycle.
Receives: Drug: Cobimetinib; Drug: Venetoclax
Dose Escalation: Arm A (Venetoclax 400mg + Cobi 60mg)ExperimentalParticipants received Venetoclax 400mg daily on Days 1-28 of each 28 day treatment cycle and Cobimetinib 60mg daily on Days 1-21 of each 28-day treatment cycle.
Receives: Drug: Cobimetinib; Drug: Venetoclax
Dose Escalation: Arm B (Venetoclax 400mg + Ida 200mg)ExperimentalParticipants received Venetoclax 400mg daily on Days 1-28 of each 28 day treatment cycle and Idasanutlin 200mg daily or twice daily on Days 1-5 of each 28 day treatment cycle.
Receives: Drug: Idasanutlin; Drug: Venetoclax
Dose Escalation: Arm B (Venetoclax 600mg + Ida 150mg)ExperimentalParticipants received Venetoclax 600mg daily on Days 1-28 of each 28 day treatment cycle and Idasanutlin 150mg daily or twice daily on Days 1-5 of each 28 day treatment cycle.
Receives: Drug: Idasanutlin; Drug: Venetoclax
Dose Escalation: Arm B (Venetoclax 600mg + Ida 200mg)ExperimentalParticipants received Venetoclax 600mg daily on Days 1-28 of each 28 day treatment cycle and Idasanutlin 200mg daily or twice daily on Days 1-5 of each 28 day treatment cycle.
Receives: Drug: Idasanutlin; Drug: Venetoclax
Dose Escalation: Arm B (Venetoclax 400mg + Ida 400mg)ExperimentalParticipants received Venetoclax 400mg daily on Days 1-28 of each 28 day treatment cycle and Idasanutlin 400mg daily or twice daily on Days 1-5 of each 28 day treatment cycle.
Receives: Drug: Idasanutlin; Drug: Venetoclax
Dose Optimisation: Arm B (Ven 600mg (Day 1 to 21) + Ida 150mg)ExperimentalParticipants received Venetoclax 600mg daily on Days 1-21 of each 28 day treatment cycle and Idasanutlin 150mg daily on Days 1-5 of each 28 day treatment cycle.
Receives: Drug: Idasanutlin; Drug: Venetoclax

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants with Dose Limiting Toxicities (DLTs)

    Measured: From Cycle 1 Day 1 to Cycle 2 Day 1 for a minimum of 28 days

  2. Number of Participants with Adverse Events (AEs), Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs)

    Measured: Baseline up until 30 days after the last dose of study drug (up to a maximum of 4 years, 9 months)

Secondary outcomes (19)

  1. Overall Response Rate (ORR) (Complete Remission (CR) + Complete Remission with Incomplete Blood Recovery (CRi) + Incomplete Platelet Count Recovery (CRp) + Partial Remission/Partial Response [PR])

    Measured: Up to 2 years

  2. Complete Remission/complete response (CR) + Complete Remission with Incomplete Blood Recovery (CRi) + Incomplete Platelet Count Recovery (CRp)

    Measured: Up to 2 years

  3. CR + Complete Remission with Partial Hematologic Recovery (CRh) Rate

    Measured: Up to 2 years

  4. Duration of Response (DOR)

    Measured: Up to 2 years

  5. Time to Progression (TTP)

    Measured: Up to 2 years

  6. Progression-Free Survival (PFS)

    Measured: Up to 2 years

  7. Event-Free Survival (EFS)

    Measured: Up to 2 years

  8. Leukemia-Free Survival (LFS)

    Measured: Up to 2 years

  9. Overall Survival (OS)

    Measured: Up to 2 years

  10. Pharmacokinetics of Venetoclax Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr)

    Measured: Up to 6 months

  11. Pharmacokinetics of Venetoclax Maximum Observed Concentration (Cmax)

    Measured: Up to 6 months

  12. Pharmacokinetics of Cobimetinib Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr)

    Measured: Up to 6 months

  13. Pharmacokinetics of Cobimetinib Maximum Observed Concentration (Cmax)

    Measured: Up to 6 months

  14. Pharmacokinetics of Idasanutlin Area Under the Concentration-Time Curve from Time Zero to Last Measurable Concentration (AUC0-24hr)

    Measured: Up to 6 months

  15. Pharmacokinetics of Idasanutlin Maximum Observed Concentration (Cmax)

    Measured: Up to 6 months

  16. Number of Participants Reporting Symptoms in Patient-Reported Outcomes of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Questionnaire

    Measured: Up to 2 years

  17. Rate of Transfusion Independence

    Measured: Up to 2 years

  18. Duration Of Transfusion Independence, Defined As The Number Of Consecutive Days Of Transfusion Independence, Measured From 1 Day After Last Transfusion To Disease Progression Or Subsequent Transfusion

    Measured: Up to 2 years

  19. Minimal Residual Disease (MRD) In The Bone Marrow To Evaluate The Depth Of Response

    Measured: Up to 2 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Feb 2016 (estimated)
  2. Study start9 Mar 2016
  3. Primary completion10 Dec 2020
  4. Study completion10 Dec 2020

Resources

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
Non-randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
88 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02670044
Sponsor's protocol ID
GH29914
Other IDs
2015-003386-28, 2015
Status last verified
Dec 2021
First submitted
28 Jan 2016
Last updated
3 Jan 2022
Results posted
No

Publications

  • Daver NG, Dail M, Garcia JS, Jonas BA, Yee KWL, Kelly KR, Vey N, Assouline S, Roboz GJ, Paolini S, Pollyea DA, Tafuri A, Brandwein JM, Pigneux A, Powell BL, Fenaux P, Olin RL, Visani G, Martinelli G, Onishi M, Wang J, Huang W, Green C, Ott MG, Hong WJ, Konopleva MY, Andreeff M. Venetoclax and idasanutlin in relapsed/refractory AML: a nonrandomized, open-label phase 1b trial. Blood. 2023 Mar 16;141(11):1265-1276. doi: 10.1182/blood.2022016362.

    PubMed 36265087

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Cobimetinib, Idasanutlin and Venetoclax in people with Leukemia, Myeloid, Acute, run by Hoffmann-La Roche at 17 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Jan 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 17 sites in United States, Canada, France, Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants with Dose Limiting Toxicities (DLTs) (time frame: From Cycle 1 Day 1 to Cycle 2 Day 1 for a minimum of 28 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02670044, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jan 2022.

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