Study of Capivasertib in Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

Phase 2

Completed

Conditions: Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

Interventions: Drug: Capivasertib

Registration Number: NCT05008055

Lead Sponsor: AstraZeneca

Brief Summary: This study is an open-label, multicenter Phase II study of capivasertib administered orally in participants with Relapsed or Refractory (R/R) B-cell Non-Hodgkin's Lymphoma (NHL).

Detailed Description: The study protocol follows a modular design. The study will investigate the safety and efficacy of capivasertib monotherapy in participants with R/R Follicular Lymphoma (FL), Marginal Zone Lymphoma (MZL), and Mantle Cell Lymphoma (MCL).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 30

Inclusion Criteria

Participants must be ≥ 18 years of age, at the time of signing the informed consent
Eastern Cooperative Oncology Group performance status ≤ 2
Life expectancy > 6 months
Female participants must not be breast-feeding and must have a negative pregnancy test (serum) prior to start of dosing

Module 1 specific inclusion criteria:

Additional Inclusion Criteria for Cohort 1A (R/R FL):

Histologically confirmed diagnosis of FL Grade 1, 2, or 3a as assessed by investigator or local pathologist
Current need for systemic treatment based on the Investigator's opinion
Relapsed, progressed or refractory (defined as failure to achieve at least a partial response [PR]) after at least 2 prior systemic lines of therapy (including anti-CD20 monoclonal antibody [mAb] and an alkylating agent)
Bi-dimensionally measurable disease on cross sectional imaging by computed tomography (CT) or magnetic resonance imaging (MRI) with at least one nodal lesion > 1.5 cm in the long axis or at least one extranodal lesion > 1 cm in long axis.

Additional Inclusion Criteria for Cohort 1B (R/R MZL):

Histologically confirmed MZL including splenic, nodal, and extranodal subtypes as assessed by investigator or local pathologist
Current need for systemic treatment based on the Investigator's opinion
Relapsed, progressed or refractory (defined as failure to achieve at least a PR) after at least 2 prior systemic lines of therapy (including at least one anti-CD20mAb directed regimen either as monotherapy or as chemoimmunotherapy; Helicobacter pylori eradication and radiation therapy alone will not be considered a systemic treatment regimen)
Bi-dimensionally measurable disease on cross sectional imaging by CT or MRI with at least one nodal lesion > 1.5 cm in the long axis or at least one extranodal lesion > 1 cm in long axis

Additional Inclusion Criteria for Cohort 1C (R/R MCL):

Histologically confirmed MCL, with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1, as assessed by investigator or local pathologist
Relapsed, progressed or refractory (defined as failure to achieve at least a PR) after at least 2 prior systemic lines of therapy
Participants must have received as prior therapies

Prior regimens must have included:
- BTK inhibitor and
- Anti-CD20mAb therapy
Bi-dimensionally measurable disease on cross sectional imaging by CT or MRI with at least one nodal lesion > 1.5 cm in the long axis or at least one extranodal lesion > 1 cm in long axis

Exclusion Criteria

Prior malignancy (other than the disease under study), except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, or other cancer from which the participant has been disease free for ≥ 2 years
With the exception of alopecia, any unresolved non-haematological toxicities from prior therapy ≥ Common Terminology Criteria for Adverse Events Grade 2 at the time of starting study treatment
Known medically apparent central nervous system lymphoma or leptomeningeal disease
Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values at screening:
1. Absolute neutrophil count < 1.0 × 10^9/L; < 0.75 × 10^9/L in participants with known bone marrow involvement of malignant disease
2. Platelets < 75 × 10^9/L; < 50 × 10^9/L in participants with known bone marrow involvement of malignant disease
3. Creatinine clearance < 50 mL/min per the Cockcroft and Gault formula
Clinically significant abnormalities of glucose metabolism as participants with diabetes mellitus type I or diabetes mellitus type II requiring insulin treatment and Glycosylated haemoglobin ≥ 8.0% (63.9 mmol/mol)
Prior treatment with any of the following:
1. Any investigational agents or study drugs from a previous clinical study within 5 half lives or 2 weeks from the first dose of capivasertib in this study
2. Strong inhibitors or inducers of CYP3A4 within 2 weeks prior to the first dose of study treatment (3 weeks for St John's wort), or drugs that are sensitive to inhibition of CYP3A4 within 1 week prior to the first dose of study treatment
3. Prior allogenic Haematopoietic stem cell transplant (HSCT) within 6 months from the first dose of capivasertib (patients > 6 months after allogenic HSCT are eligible in the absence of active graft-versus-host disease and concomitant immune suppressive therapy). Prior cellular therapies (eg, Chimeric antigen receptor T therapy) and/or autologous HSCT within 3 months from the first dose of capivasertib
4. Receipt of live, attenuated vaccine within 28 days before the first dose of study treatment(s)
5. Participants who, due to other medical conditions /prior history /concomitant medications are, in the investigator's opinion, at a risk of a venous thromboembolism (VTE) and are not willing to accept the VTE prophylaxis, will be excluded. The initiation of an adequate VTE prophylaxis will be based on treating physician risk/benefit assessment and in agreement with the local management guidelines

Additional exclusion core criteria may apply, please refer to the protocol

Module 1 specific exclusion criteria:

Follicular lymphoma grade 3B
Known transformation to aggressive lymphoma, eg, large cell lymphoma
Participants who, in the Investigator's opinion, require immediate cytoreductive therapy for disease control

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Capivasertib monotherapy	Capivasertib	Participants with R/R FL, R/R MZL, and R/R MCL will receive capivasertib orally until progression of disease (PD) or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Objective Response Rate	First dose until progression of disease [PD] or last evaluable assessment in the absence of progression or data cut-off date (21.6 Months)	Objective response rate is defined as the proportion of patients achieving either complete response (CR) or partial response (PR) according to the Lugano 2014 Classification for non-Hodgkin lymphoma (NHL) as assessed by blinded independent central review (BICR).

Secondary Outcome Measures

Name	Time	Method
Duration of Response	First documented response until date of documented progression or data-cut off date (21.6 Months)	Duration of response is defined as the time from the date of first documented response until date of documented progression according to the Lugano 2014 Classification for NHL as assessed by BICR, or death due to any cause.
Progression-free Survival	First dose until documented disease progression or data cut-off date (21.6 Months)	Progression-free survival is defined as the time from the date of first dose until documented disease progression according to the Lugano 2014 Classification for NHL as assessed by BICR, or death due to any cause. The analysis included all dosed patients, regardless of whether the patient withdrew from therapy, received another anti lymphoma therapy, or clinically progressed prior to progression according to the Lugano 2014 Classification for NHL.
Overall Survival (OS)	First dose until data cut-off date (21.6 Months)	Overall survival is defined as time from the date of first dose until the date of death due to any cause. The analysis included all dosed patients, regardless of whether the patient withdrew from therapy or received another anti lymphoma therapy. Patients who had not died by the analysis DCO date were censored at their last known date of being alive before the DCO date. Patients who were known to be alive or dead after the DCO date were censored at the DCO date. Patients who were lost to follow-up were censored at the date when they were last known to have been alive.
Number of Patients With Adverse Events and Serious Adverse Events	Screening (Day -28 to -1) until Post-treatment follow-up up to 30 days after last dose or long-term follow-up or study completion (Every 12 weeks until death or lost to follow-up, unless patient have withdrawn consent [up to 21.6 Months])	The safety and tolerability of the capivasertib treatment in each Cohort was assessed.
Plasma Concentration of Capivasertib Overtime	Cycle 1 (28-day treatment Cycle) Day 1 and on Cycle 1 Day 8, Cycle 1 Day 15 and Cycle 1 Day 22 (Pre-dose and post-dose)	The plasma concentration of capivasertib when administered in patients in each Cohort was determined.