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Chronic Lymphocytic LeukemiaPhase 1RIVe-CLL/SLLNCT03639324

Rituximab, Idelalisib, and Venetoclax in Relapsed/Refractory CLL/SLL

A Phase 1 study testing Dose combination 1-1, dose combination 1-2 and Dose combination 1-3 in people with Chronic Lymphocytic Leukemia and CLL, run by Virginia Commonwealth University.

Withdrawn

Withdrawn. The study stopped before anyone enrolled.

Official record
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Trial summary

To determine the recommended phase 2 dose (RP2D) of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory Chronic lymphocytic leukemia/ Small lymphocytic lymphoma (CLL/SLL) following a lead-in period with idelalisib and rituximab Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Chronic Lymphocytic Leukemia, CLL, Relapsed CLL
What is being tested?
Dose combination 1-1, dose combination 1-2 and Dose combination 1-3
Could I receive a placebo?
No, everyone receives an active treatment
How many people
0 participants
Where
No sites listed yet
Study dates
2 Oct 2020to 18 Oct 2021
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

  • Age ≥ 18 years of age. Relapsed or refractory B-cell CLL or biopsy-proven SLL. Treatment required in the opinion of the investigator
  • Must have had at least one standard treatment with a regimen containing at least one of the following agents/classes of agents; and where specified, must also meet the treatment duration, progression, and/or relapse criteria for that class of agent:
  • Fludarabine
  • An alkylator (eg, chlorambucil, bendamustine)
  • A BTK inhibitor (eg, ibrutinib, acalabrutinib); and must have progressed or relapsed > 6 months after last BTK inhibitor treatment
  • An anti-CD20 monoclonal antibody (eg, rituximab, obinutuzumab)
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  • A BCL-2-family protein inhibitor (eg, venetoclax, navitoclax); and
  • if best response is < CR with BCL-2-family protein inhibitor treatment
  • must have had ≥ 1 year of BCL-2-family protein inhibitor treatment; and
  • must have progressed > 6 months after last BCL-2-family protein inhibitor treatment
  • if best response is CR with BCL-2-family protein inhibitor treatment
  • must have relapsed ≥ 1 year after last BCL-2-family protein inhibitor treatment
  • A PI3K inhibitor (eg, idelalisib, duvelisib, TGR-1202, copanlisib, buparlisib); and must have progressed or relapsed > 6 months after last treatment with the PI3K inhibitor (NOTE THAT THIS CRITERION IS NOT APPLICABLE TO 2ND-STEP REGISTRATION)
  • Prior allogeneic stem cell transplant allowed provided the following criteria are met:
  • ≥ 12 months have elapsed since allogeneic transplant
  • No current or prior evidence of graft-versus-host disease
  • No current requirement for immunosuppressive therapy Prior autologous stem cell transplant allowed provided ≥ 6 months have elapsed since autologous transplant.
  • Eastern Cooperative Oncology Group performance status of 0, 1, or 2
  • Adequate bone marrow function as follows:
  • Absolute neutrophil count (ANC) ≥ 1,000/mm3 (without support of granulocyte colony stimulating factors)
  • Platelets ≥ 50,000/mm3 (untransfused)
  • Hemoglobin ≥ 9.0 g/dL
  • Adequate coagulation, renal, and hepatic function as follows:
  • aPTT and PT ≤ 1.2 × upper limit of normal (ULN) for the laboratory
  • Calculated creatinine clearance ≥ 50 mL/min as calculated by the standard Cockcroft-Gault equation using age, actual weight, creatinine, and gender
  • AST and ALT ≤ 1.5 × ULN for the laboratory
  • Bilirubin ≤ 1.5 × ULN for the laboratory. For a woman of childbearing potential (WCBP), a negative serum pregnancy test performed within 7 days prior to initiation of study treatment.
  • Note: Postmenopausal is defined as any of the following:
  • Age ≥ 60 years
  • Age < 60 years and amenorrheic for at least 1 year with follicle-stimulating hormone (FSH) and plasma estradiol levels in the postmenopausal range
  • Bilateral oophorectomy WCBP and male patients must agree to use a medically accepted form of birth control for the duration of study treatment and for at least 1 month following completion of venetoclax and/or idelalisib or 12 months following rituximab, whichever occurs later.
  • Ability to understand and the willingness to sign a written informed consent document.

Who cannot join

  • A patient who meets any of the following exclusion criteria is ineligible to participate in the study:
  • Known histologic transformation from CLL/SLL to an aggressive lymphoma (ie, Richter's transformation).
  • Known history of drug-induced pneumonitis History of inflammatory bowel disease. Central nervous system involvement Clinically significant infection including active hepatitis B or hepatitis C requiring active treatment, or active CMV infection Known human immunodeficiency virus (HIV) seropositivity. Note: HIV testing is not required.
  • Vaccination within 4 weeks prior to initiation of rituximab Note: Review vaccination status. Patients should, if possible, be brought up-to-date with all immunizations in agreement with current immunization guidelines at least 4 weeks prior to initiating rituximab.•Ongoing requirement for warfarin (due to potential drug-drug interactions that may increase the exposure of warfarin and ensuing complications).
  • Has received any of the following within 14 days prior to initiation of study treatment:(NOTE THAT THIS CRITERION IS NOT APPLICABLE TO 2ND-STEP REGISTRATION)
  • Anti-cancer therapy
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  • Investigational therapy Has not recovered to ≤ grade 1 toxicity(s) from prior therapy, except for chronic residual toxicities that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profiles of the study regimen (eg, alopecia). (NOTE THAT THIS CRITERION IS NOT APPLICABLE TO 2ND-STEP REGISTRATION) Has not recovered to ≤ grade 1 toxicity(s) from idelalisib and rituximab, except for chronic residual toxicities that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profiles of the study regimen (eg, alopecia). (NOTE THAT THIS CRITERION IS NOT APPLICABLE TO 1ST-STEP REGISTRATION)
  • Ongoing or planned treatment with any of the following:
  • Steroid therapy for anti-neoplastic intent
  • Strong or moderate CYP3A inhibitor or inducer, and/or a narrow-therapeutic sensitive substrate
  • P-gp inhibitor or narrow-therapeutic sensitive P-gp substrate If any of these agents have been used, patients must be off them for ≥ 1 week before initiation of study treatment.
  • Prior intolerance to any component of study regimen that, in the opinion of the investigator would preclude study treatment.
  • A cardiovascular disability status of New York Heart Association Class ≥ II Diagnosis or treatment for another malignancy within 1 year of study registration, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, any in situ malignancy, or low-risk prostate cancer after curative therapy Active liver disease other than lymphoid involvement, inflammatory bowel disease, or Crohn's disease Malabsorption syndrome or other condition that precludes enteral route of administration.
  • Exhibits evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
  • Uncontrolled infection (viral, bacterial, or fungal)
  • Grade 3 or greater neutropenic fever within 1 week prior to initiation of study treatment Active autoimmune cytopenias (for 2 or more weeks), including autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura.
  • Pregnancy or breastfeeding Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk, interfere with the patient's participation in the study or hinder evaluation of study results

About this study

Official title: Phase 1 Trial of Rituximab, Idelalisib, and Venetoclax in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RIVe-CLL/SLL)

To determine the recommended phase 2 dose (RP2D) of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory Chronic lymphocytic leukemia/ Small lymphocytic lymphoma (CLL/SLL) following a lead-in period with idelalisib and rituximab

Read the detailed description

This phase 1, multicenter, dose-escalation study is designed to find the Recommended Phase 2 Dose (RP2D) of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory CLL/SLL and to assess the clinical activity of the combination with rituximab in patients with relapsed or refractory CLL/SLL and to assess the clinical activity of the combination.

Being tested
Dose combination 1-1, dose combination 1-2, Dose combination 1-3, dose combination 1-4, Sub-Trial: Dose combination 2-1
Keywords
venetoclax, idelalisib, rituximab
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

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

  • Dose combination 1-1Drug

    100 mg QD of idelalisib + 100 mg QD of venetoclax

  • dose combination 1-2Drug

    100 mg QD of idelalisib + 200 mg QD of venetoclax

  • Dose combination 1-3Drug

    100 mg BID of idelalisib + 200 mg QD of venetoclax

  • dose combination 1-4Drug

    150 mg BID of idelalisib + 200 mg QD of venetoclax

  • Sub-Trial: Dose combination 2-1Drug

    100 mg BID of idelalisib + 100 mg QD of venetoclax

  • Sub-Trial: Dose combination 2-2Drug

    150 mg BID of idelalisib + 100 mg QD of venetoclax

Study groups in NCT03639324
Study groupRoleWhat they receive
Dose Combination 1-1Experimentalidelalisib + venetoclax
Receives: Drug: Dose combination 1-1
Dose Combination 1-2Experimentalidelalisib + venetoclax
Receives: Drug: dose combination 1-2
Dose Combination 1-3Experimentalidelalisib + venetoclax
Receives: Drug: Dose combination 1-3
Dose Combination 1-4Experimentalidelalisib + venetoclax
Receives: Drug: dose combination 1-4
Sub-Trial Dose Combination 2-1Experimentalidelalisib + venetoclax
Receives: Drug: Sub-Trial: Dose combination 2-1
Sub-Trial Dose Combination 2-2Experimentalidelalisib + venetoclax
Receives: Drug: Sub-Trial: Dose combination 2-2

What is being measured

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

  1. Find the RP2D of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL)

    Determine the recommended phase 2 dose of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory CLL/SLL following a lead-in period with idelalisib and rituximab.

    Measured: 41 Months

Secondary outcomes (7)

  1. Safety Evaluation: Determine adverse events (AEs) reported using criteria in the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0

    Observed adverse events of treatment with idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory CLL/ SLL following a lead-in period with idelalisib and rituximab utlizing CTCAE Version 5.0

    Measured: 63 Months

  2. Determination of cumulative complete response (CR) rate.

    Determine the cumulative CR rate to the study regimen at 7 and 13 months using the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria.

    Measured: 52 Months

  3. Summarize the objective response rate.

    Determine the cumulative overall disease response to the study regimen at 7 and 13 months using the 2008 IWCLL criteria.

    Measured: 52 Months

  4. Minimal residual disease (MRD) rate

    Estimate the rate of undetectable minimal residual disease (MRD) status for idelalisib and venetoclax in combination with rituximab using 4-color flow cytometry in peripheral blood and/or bone marrow for responding patients

    Measured: 52 Months

  5. Overall Survival Rate

    determine the OS rate (at 24 months following initiation of venetoclax) for idelalisib and venetoclax in combination with rituximab.

    Measured: 63 Months

  6. Progression Free Survival Rate

    Determine the progression-free survival (PFS) rate (at 24 months following initiation of venetoclax) for idelalisib and venetoclax in combination with rituximab

    Measured: 63 Months

  7. Pharmacokinetics of the combination of idelalisib and venetoclax.

    Determine the idelalisib and venetoclax plasma concentrations measured at designated time points throughout the study: pre-Tx; C1D1; C1D15; C1D22; C1D29; C3D1; C7D22; C13D222; at DLT (if feasible); at relapse (if feasible)]

    Measured: 7 Years

Timeline

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

  1. First posted21 Aug 2018
  2. Study start2 Oct 2020
  3. Primary completion18 Oct 2021
  4. Study completion18 Oct 2021

Why it stopped: Slow Accrual

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
Sequential
Model description
Patients will start on dose level 1 of venetoclax in combination with rituximab and idelalisib, then escalate or de-escalate (if lower dose is available) based upon the estimated probabilities of toxicity from an extension of the continual reassessment method for 2 agents.
Masking
None (open label)
Enrolment
0 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03639324
Sponsor's protocol ID
MCC-15-12310
Other IDs
NCI-2018-01661
Acronym
RIVe-CLL/SLL
Status last verified
Nov 2021
First submitted
8 Aug 2018
Last updated
9 Nov 2021
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Dose combination 1-1, dose combination 1-2 and Dose combination 1-3 in people with Chronic Lymphocytic Leukemia and CLL, run by Virginia Commonwealth University.

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 32 inclusion and 17 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: withdrawn, as of the sponsor's last update on 9 Nov 2021. Status can change between updates, so confirm with the study contact before making plans.

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 was withdrawn before enrolling participants, so there are no results.

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?

Find the RP2D of idelalisib and venetoclax in combination with rituximab in patients with relapsed or refractory chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/SLL) (time frame: 41 Months). 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 NCT03639324.

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 9 Nov 2021.

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