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

Study Overview
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Brief Summary
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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
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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).

Official Title
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A Modular Phase II, Open-Label, Multicentre Study to Assess the Efficacy and Safety of Capivasertib in Patients With Relapsed or Refractory B-cell Non-Hodgkin Lymphoma (CAPITAL)

Conditions
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Relapsed or Refractory B-cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Capivasertib


Participation Criteria
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Eligibility Criteria
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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: Absolute neutrophil count < 1.0 × 10^9/L; < 0.75 × 10^9/L in participants with known bone marrow involvement of malignant disease Platelets < 75 × 10^9/L; < 50 × 10^9/L in participants with known bone marrow involvement of malignant disease 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: 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 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 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 Receipt of live, attenuated vaccine within 28 days before the first dose of study treatment(s) 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Capivasertib monotherapy<br>Participants with R/R FL, R/R MZL, and R/R MCL will receive capivasertib orally until progression of disease (PD) or unacceptable toxicity. | Drug: Capivasertib<br>* Capivasertib will be taken orally twice a day (BD) 4 days on/ 3 days off.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with objective response | Estimation of effectiveness of the capivasertib by assessment of objective response rate (ORR). The ORR is defined as the proportion of participants achieving either complete response (CR) or partial response (PR) according to the Lugano 2014 Classification for NHL as assessed by blinded independent central review (BICR). | Until progression of disease [PD] or last evaluable assessment in the absence of progression (Assessed Up to 1.6 Years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DoR) | Estimation of effectiveness of the capivasertib by assessment of DoR. The DoR 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 in the absence of disease progression. | Screening (days -28 to -1), Weeks 8, 16, 24, 36, 48, and 60 and thereafter every 24 weeks for FL/MZL and every 12 weeks for MCL, until PD (Assessed Up to 1.6 Years) | 
| Progression-free survival | Estimation of effectiveness of the capivasertib by assessment of progression-free survival. 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 in the absence of disease progression. | Screening (days -28 to -1), Weeks 8, 16, 24, 36, 48, and 60 and thereafter every 24 weeks for FL/MZL and every 12 weeks for MCL, until PD (Assessed Up to 1.6 Years) | 
| Overall survival (OS) | Estimation of effectiveness of the capivasertib by assessment of OS. Overall survival is defined as time from the date of first dose until the date of death due to any cause. | Until Death due to any cause (Assessed Up to 1.6 Years) | 
| Change from baseline in health-related quality of life as measured by European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) | Assessment of patient-reported disease-related symptoms, functioning and health-related quality of life as measured by EORTC QLQ-C30. | Cycle 1 (28-day treatment Cycle) Day 1 and every 4 weeks from Cycle 1 Day 1 for the first 24 weeks and then every 12 weeks thereafter until 12 weeks post progression | 
| Proportion of participants reporting symptomatic adverse events (AEs) and overall side effect burden at each time point as measured by Patient Global Impression of Treatment Tolerability (PGI-TT) | Assessment of patient-reported symptomatic AEs as measured by PGI-TT. | Cycle 1 (28-day treatment Cycle) Day 1, every week from Cycle 1 Day 1 for the first 4 weeks, every 4 weeks for the next 8 weeks, and every 12 weeks afterwards until EOT and Post treatment follow-up (Assessed Up to 1.6 Years) | 
| Proportion of patients reporting symptomatic AEs and overall side effect burden at each time point as measured by patient-reported outcomes common terminology criteria for adverse events (PRO-CTCAE) | Assessment of patient-reported symptomatic AEs/tolerability of capivasertib as measured by PRO-CTCAE. | Cycle 1 (28-day treatment Cycle) Day 1, every week from Cycle 1 Day 1 for the first 4 weeks, every 4 weeks for the next 8 weeks, and every 12 weeks afterwards until EOT and Post treatment follow-up (Assessed up to 1.6 Years) | 
| Time to first subsequent therapy or death (TFST) | Estimation of the effectiveness of capivasertib by TFST. The TFST is defined as time from date of first dose until the start date of first subsequent anti-lymphoma therapy after discontinuation of study treatment or death due to any cause. | Until first subsequent anti-lymphoma therapy or Death due to any cause (Assessed Up to 1.6 Years ) | 
| Time to objective response (TTR) | Estimation of effectiveness of the capivasertib by assessment of TTR. The TTR is defined as as time from date of first dose until the date of first documented objective response per the Lugano 2014 Classification for NHL as assessed by BICR. | From Cycle 1 (28-day treatment cycle) Day 1 until documented response (also until PD/Death for those who never respond) [Assessed Up to 1.6 Years] | 
| Number of participants with AEs and Serious adverse events | Assessment of safety and tolerability of the capivasertib. | Screening (Day -28 to -1) until Post-treatment follow-up (30 days after last dose) or long-term follow-up (Every 12 weeks) [Assessed up to 1.6 Years] | 
| Observed lowest drug concentration reached before the next dose is administered (Ctrough) of capivasertib | Determination of plasma concentration of capivasertib pre-dose (Ctrough). | Pre-dose on Cycle 1 (28-day treatment Cycle) Day 1 and on Cycle 1 Day 8, Cycle 1 Day 15 and Cycle 1 Day 22 | 
| Plasma concentration of capivasertib post-dose | Determination of plasma concentration of capivasertib post-dose | Cycle 1 (28-day treatment Cycle) Day 1: 1 hour, 2 hour and 4 hour post-dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Follicular Lymphoma, Marginal Zone Lymphoma, Mantle Cell Lymphoma, Capivasertib monotherapy