Step-Wise Combination of Obinutuzumab, Vemurafenib and Cobimetinib in Patients with Hairy Cell Leukemia (Hcl) Previously Treated with Purine Analogs or Unfit for Chemotherapy: a PHASE-2, Single-Arms, Italian, Multicenter Study (HCL-PG04)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universita' Degli Studi Di Perugia

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

28 Jan 2025 → ongoing

Decision date (initial)

2025-01-28

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Università degli Studi di Perugia, Dipartimento di Medicina e Chirurgia · Roche S.p.A

External identifiers

EU CT number

2024-520121-36-00

EudraCT number

2017-001836-20

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

To determine the depth of anti-leukemic activity of the study drugs vemurafenib, cobimetinib and obinutuzumab in three distinct cohorts of eligible HCL patients carrying the BRAF-V600E mutation and receiving the study drugs in step-wise combinations (Cohort-1/Phase-A, Cohort-1/Phase-B, Cohort-2 and Cohort-3).

Secondary objectives 3

1. To assess the safety
2. To determine the rapidity and duration of anti-leukemic activity of the study drugs in each cohort
3. To determine the efficacy of further anti-leukemic treatments that the patients might receive after those planned in the current study.

Conditions and MedDRA coding

The following categories of HCL patients needing anti-leukemic treatment are eligible for inclusion in this protocol: 1) Patients whose disease is refractory to therapy with purine analogues (no CR no PR, or relapse ≤1 year following treatment). 2) Patients who relapse early (≥1 year and ≤2 years) after the first course of a purine analogue (pentostatin or cladribine), or who relapse whenever after a second or later course. If the first relapse is accompanied by bone marrow hypoplasia (<20% hematopoietic cells on histological analysis), which would advise against chemotherapy with a purine analogue, the patient is eligible even if the relapse occurs >2 years after the first course. 4) Patients who: i) manifested severe side effects from a previous therapy with purine analogues (including, but not limited to, prolonged and profound myelosuppression and immunosuppression, infectious complications, renal failure, vasculitis; autoimmune hemolytic anemia); or ii) are deemed by the investigator medically unfit for chemotherapy with purine analogues (for example because of old age and/or significant comorbidities); or iii) firmly refuse to undergo chemotherapy (for example because they are Jehovah's witnesses and want to avoid any chemotherapy-induced need of blood product transfusions); or iv) have an active infection which would make chemotherapy with purine analogs risky; in this case patients enrolled in a cohort where obinutuzumab is planned (Cohort-1/Phase-A, Cohort-1/Phase-B and Cohort-3) are allowed to start vemurafenib with or without cobimetinib immediately, whereas obinutuzumab should be started only after the active infection has been controlled.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 1. Male or female HCL patients ≥ 18 years of age.
2. 2. Proven diagnosis of HCL according to the morphological and immunophenotypic criteria (co-expression of CD11c/CD25/CD103 and/or positivity for annexin-A1) of the World Health Organization (WHO-2008) classification of lymphoid neoplasms12, accompanied by the presence of the BRAF-V600E mutation as detected using a sensitive allele-specific polymerase chain reaction (AS-PCR) recently developed in our laboratory
3. 3. Patients with HCL must fall in one of the categories indicated in the “Overview” of study population.
4. 4. Any prior treatment (chemotherapy and/or immunotherapy) must have been completed at least 12 weeks prior to initiation of study medication, except if no response to this treatment is already manifestly evident earlier.
5. 5. ECOG performace status 0-2.
6. 6. Patients must have recovered from all side effects of their most recent treatment for HCL.
7. 7. Negative serum pregnancy test within 14 days prior to commencement of dosing in premenopausal women. Women of non-childbearing potential may be included if they are either surgically sterile or have been postmenopausal for ≥1 year.
8. 8. Fertile men and women must use an effective method of contraception during treatment and for at least 16 weeks (for men) and 12 months (for women) after completion of treatment as directed by their physician. Effective methods of contraception are defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly (for example implants, injectables, or intrauterine devices). Oral contraceptives are not reliable due to potential drug-drug interaction. At the discretion of the investigator, acceptable methods of contraception may include total abstinence in cases where the lifestyle of the patient ensures compliance. Periodic abstinence (e.g. calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
9. 9. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before trial entry.
10. 10. Signed informed consent must be obtained prior to performing any study-related procedures.
11. 11. Clinical indication for treatment, i.e. the presence of one or more of the following: neutrophils <1.5x109 per liter, hemoglobin <11 g per deciliter, platelets <100x109 per liter, bulky and/or symptomatic splenomegaly, clinically relevant infiltration of other organs (e.g., lymphadenopathy), recurrent disease-related opportunistic infections.

Exclusion criteria 10

1. 1. Concurrent administration of any anti-cancer therapies (e.g. chemotherapy, other targeted therapy, experimental drug, etc.) other than those administered in this study and concurrent treatment on another therapeutic clinical trial.
2. 2. Pregnant (negative serum pregnancy test is required in women of child-bearing potential) or lactating women.
3. 3. Refractory nausea and vomiting, malabsorption, external biliary shunt, or significant bowel resection that would preclude adequate absorption. Patients must be able to swallow tablets.
4. 4. History of congenital long QT syndrome
5. 5. Corrected QT (QTc) interval ≥500 msec at baseline or uncorrectable electrolyte abnormalities.
6. 6. Active hepatitis infection.
7. 7. Uncontrolled medical illness.
8. 8. Other severe, acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, or which in the judgment of the investigator would make the patient inappropriate for entry into this study.
9. 9. Unwillingness to practice effective birth control.
10. 10. Inability to comply with other requirements of the protocol

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1. The primary endpoint in each cohort is to meet or exceed a pre-determined rate of response (complete or overall response as specified later for each cohort) according to a per-protocol analysis. The rate of response will be also calculated according to the intention-to-treat analysis for informative purpose only, because this is a phase- 2 non-randomized trial primarily designed to test the anti-leukemic activity of the study drugs.

Secondary endpoints 2

1. 1. To describe the type, incidence, grade and relationship to the study drugs of adverse events (AE) occurring in each cohort.
2. 2. To describe separately in each cohort: the time to response; the relapse-free survival (or response duration); the treatment-free survival; the progression-free survival; the event-free survival; the disease-specific survival; the overall survival; the specific type of, and response to, other anti-leukemic treatments.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universita' Degli Studi Di Perugia

Sponsor organisation

Universita' Degli Studi Di Perugia

Address

Piazza Dell' Universita' 1

City

Perugia

Postcode

06123

Country

Italy

Scientific contact point

Organisation

Universita' Degli Studi Di Perugia

Contact name

Enrico Tiacci

Public contact point

Organisation

Universita' Degli Studi Di Perugia

Contact name

Enrico Tiacci

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications