Study of Lenalidomide, Venetoclax and Obinutuzumab in Patients With Treatment-Naïve Follicular Lymphoma

NCT03980171 | Active Not Recruiting Phase 1 DMC

• 1 other identifier: 19/45
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 3

Brief Summary

The trial will investigate the combination of venetoclax, obinutuzumab and lenalidomide in patients with treatment-naïve follicular lymphoma. Patients will receive induction treatment for 0.5 years with venetoclax, obinutuzumab and lenalidomide followed by maintenance treatment for upto 2 years. Maintenance treatment will be determined by the response at the end of induction. Following completion of treatment patients will be followed up for 3 years after the last patient completes induction treatment.

Conditions

Follicular Lymphoma

Outcome Measures

Primary Outcomes (12)

• Dose limiting toxicities (DLT)

  A toxicity that prevents further administration of the trial treatment at that dose level.

  During the first 2 cycles of induction during dose escalation which is expected to be completed in 1.5 years.

• Recommended phase II dose (RP2D) of venetoclax in combination with lenalidomide and obinutuzumab

  The highest dose level at which the incidence of DLT was less than 2/6

  During dose escalation (1.5 years)

• Complete response (CR) at the end of induction

  Investigator assessed CR rate by PET-CT after induction (end of cycle 6) by 2014 Lugano criteria

  3.5 years from first patient commencing treatment

• Adverse events (AEs) of venetoclax, lenalidomide and obinutuzumab

  Type, grade and relationship to treatment of AEs, assessed according to Common Terminology of Coding of Adverse Events (CTCAE) v5.0.

  From signing consent until after completion of study treatment (6.75 years)

• Rate of treatment-emergent AEs that require discontinuation or dose modification of study drug

  Type and grade of treatment-emergent AEs, assessed according to CTCAE v5.0, requiring discontinuation of study drug or dose reductions or interruptions

  From signing consent until after completion of study treatment (6.75 years)

• Overall response rate (ORR)

  Investigator assessed ORR (complete response (CR) or partial response (PR)) by PET-CT assessed by 2014 Lugano criteria after 6 cycles of induction treatment (0.5 years)

  3.5 years from first patient commencing treatment

• CR at 2.5 years from commencement of induction treatment

  CR based on 2014 Lugano criteria

  5.5 years from first patient commencing treatment

• Progression free survival (PFS)

  PFS will be defined as the time from enrolment date to the first date of objectively documented progressive disease (PD) or date of death from any cause. Patients without documented progressive disease and who have not died by the end of the study will be censored at the date of last disease assessment.

  From commencement of treatment to end of study (6.75 years)

• Duration of response (DOR)

  DOR will be measured in the subset of patients who achieved CR or PR and it is defined as the time from the first documented disease response to the earliest recurrence or progressive disease. Deceased patients without recurrence or progressive disease will be censored at the date of death.

  From commencement of treatment to end of study (6.75 years)

• Time to next anti-lymphoma treatment (TTNT)

  TTNT will be measured from enrolment date to date of initiation of next anti-cancer therapy (for follicular lymphoma) or date of death from any cause. Patients who do not start next anti-cancer therapy by the end of the study will be censored at the date of last contact.

  From commencement of treatment to end of study (6.75 years)

• Overall survival (OS)

  OS will be measured from enrolment date to the date of death from any cause. Patients who have not died by the study close-out date will be censored at their last visit date. Patients who are lost to follow-up before the close-out date and who are not known to have died will be censored at the date they were last known to be alive.

  From commencement of treatment to end of study (6.75 years)

• Quality of life (QoL)

  QoL will be measured using Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym). The FACT-Lym is a disease-specific 42-item questionnaire that has been validated for the purpose of assessing health-related quality of life (HRQoL) in patients with various forms of lymphoma.The FACT-Lym consists of FACT-G subscales: Physical Well-Being (7 items), Social/Family Well-Being (7 items), Emotional Well-Being (6 items), Functional Well-Being (7 items), and the Lymphoma subscale: Additional Concerns (15 items). FACT-Lym questions are scored on a 5-point Likert scale from 0 to 4 (0 being not at all and 4 being very much).

  From commencement of treatment to end of treatment (5.5 years)

Study Arms (1)

Obinutuzumab+venetoclax+lenalidomide

EXPERIMENTAL

Patients in both dose escalation and dose expansion will receive 6 cycles of induction treatment consisting of obinutuzumab (flat dose of 1000mg) and protocol defined dose levels of venetoclax and lenalidomide.

Drug: Obinutuzumab; Drug: Venetoclax; Drug: Lenalidomide

Interventions

Obinutuzumab DRUG

A flat dose of 1000mg IV will be given every cycle during induction. a cycle is 28 days.During maintenance 1000mg IV will be given every second cycle for upto 2 years.

Also known as: GAZYVA, GAZYVARO

Obinutuzumab+venetoclax+lenalidomide

Venetoclax DRUG

During dose escalation, the doses for venetoclax can be 400mg daily days 1-10, 800mg daily days 1-10, 400mg daily continuous or 800mg daily continuous. 6 cycles of treatment will be given during induction. Once the recommended phase 2 dose (RP2D) is established that dose will be used in dose expansion. A further 6 cycles of venetoclax will be given during maintenance if required based on response at the end of induction.

Also known as: ABT-199 (A-1195425.0), Venclexta, Venclyxto

Obinutuzumab+venetoclax+lenalidomide

Lenalidomide DRUG

During dose escalation, the doses of lenalidomide can be 15mg for days 1-21 or 20mg for days 1-21. 6 cycles of treatment will be given during induction. During maintenance the dose of lenalidomide will be 10mg continuous for a further 6 cycles if required based on response at the end of induction.

Also known as: Revlimid

Obinutuzumab+venetoclax+lenalidomide

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patient has provided written informed consent.
• Patient has histologically confirmed follicular lymphoma WHO grade 1-3A and non-contiguous or bulky (\>7cm) stage II and stage III or IV according to Lugano criteria 2014, irrespective of FLIPI score
• Patient meets ≥1 Groupe d'Etude des Lymphomes Folliculaires (GELF) criterion for treatment.
• Bi-dimensionally measurable disease, with at least one mass lesion ≥ 2 cm in longest diameter.
• Male or female age ≥ 18 years at signing consent
• Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Adequate organ and haematologic function within 10 days prior to registration, defined by:
• Haemoglobin ≥80g/L
• ANC ≥1 x 109/L and platelet count ≥75 x 109/L; unless due to marrow infiltration or hypersplenism (in which case ANC ≥ 0.5 x 109/L and platelets ≥ 50 x 109/L)
• Serum aspartate transaminase (AST) or alanine transaminase (ALT) \<2.5 x upper limit of normal (ULN)
• International normalized ratio \>1.5 x ULN for patients not receiving therapeutic anticoagulation
• Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤1.5 x ULN unless due to the presence of an inhibitor (e.g. lupus anticoagulant)
• Bilirubin \<2.0 x ULN unless due to Gilbert's syndrome, documented liver involvement with lymphoma, or of non-hepatic origin
• Creatinine clearance ≥50ml/min(Cockcroft-Gault)
• Able to comply with protocol requirements and follow-up procedures.

You may not qualify if:

• WHO grade 3B follicular lymphoma, biopsy proven or clinically suspected histologic transformation to diffuse large B-cell lymphoma
• Known central nervous system lymphoma or leptomeningeal disease.
• History of other malignancy that could affect compliance with the protocol or interpretation of results Patients with a history of curatively treated basal or squamous cell carcinoma or Stage 1 melanoma of the skin or in situ carcinoma of the cervix are eligible.
• Patients with a malignancy that has been treated with curative intent may be included provided they remain in remission without treatment for ≥ 2 years prior to enrollment
• Has had prior systemic therapy for follicular lymphoma (with the exception of corticosteroid monotherapy to control disease related symptoms).
• Major surgery or a wound that has not fully healed within 4 weeks prior to registration.
• Patient is unable to swallow tablets.
• Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety, interfere with the absorption or metabolism of venetoclax or lenalidomide capsules, or put the study outcomes at undue risk.
• Known hypersensitivity to any of the study drugs or their components (obinutuzumab, L-histidine, L-histidine hydrochloride monohydrate, Trehalose dehydrate, Poloxamer 188), humanized or murine monoclonal antibodies, xanthine oxidase inhibitors or rasburicase.
• Has received the following agents within 7 days prior to registration:
• Steroid therapy with anti-neoplastic intent (with the exception of ≤7 days of prednisolone or equivalent at doses of ≤100mg daily to control lymphoma symptoms prior to cycle 1 day 1)
• Strong CYP3A inhibitors (See section 7.10.3)
• Strong CYP3A inducers (See section 7.10.3)
• Consumed grapefruit, grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days of registration
• Has a history of stroke or intracranial hemorrhage within 6 months prior to registration.

Sponsors & Collaborators

• Peter MacCallum Cancer Centre, Australia: lead

Study Sites (3)

Townsville Hospital and Health Services

Townsville, Queensland, Australia

Location

Peter MacCallum Cancer Centre

Melbourne, Victoria, 3000, Australia

Location

Sir Charles Gairdner Hospital

Nedlands, Western Australia, 6009, Australia

Location

MeSH Terms

Conditions

Lymphoma, Follicular

Interventions

obinutuzumab; venetoclax; Lenalidomide

Condition Hierarchy (Ancestors)

Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 5, 2019
• First Posted: June 10, 2019
• Study Start: August 19, 2019
• Primary Completion (Estimated): November 1, 2026
• Study Completion (Estimated): November 1, 2026
• Last Updated: July 29, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

AU (3)