| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory B-cell Non-Hodgkin Lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10067070 |
| E.1.2 | Term | Follicular B-cell non-Hodgkin's lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10076596 |
| E.1.2 | Term | Marginal zone lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061275 |
| E.1.2 | Term | Mantle cell lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To estimate the effectiveness of the module-defined study treatment by assessment of Objective Response Rate (ORR) based on Lugano 2014 Classification response criteria in each cohort as determined by Blinded Independent Central Review (BICR) |
|
| E.2.2 | Secondary objectives of the trial |
1. To estimate the effectiveness of the module-defined study-treatment by assessment of Duration of Response (DoR)
2. To estimate the effectiveness of the module-defined study treatment by assessment of Progression-Free Survival (PFS)
3. To estimate the effectiveness of the module-defined study treatment by assessment of Overall Survival (OS)
4. To assess patient-reported disease-related symptoms, functioning and health-related quality of life of the module-defined study treatment
5. To assess patient-reported symptomatic AEs / tolerability of module-defined study treatment
6. To estimate the effectiveness of the module-defined study treatment by assessment of Time to First Subsequent therapy or death (TFST) in each cohort
7. To estimate the effectiveness of the module-defined study treatment by assessment of time to objective response (TTR) in each cohort
8. To assess safety and tolerability of the module-defined study treatment
9. To determine the PK of Capivasertib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Patient must be ≥ 18 years of age, at the time of signing the informed consent
- ECOG performance status ≤ 2
- Life expectancy > 6 months
- Female patients must not be breast-feeding and must have a negative pregnancy test prior to start of dosing
Additional core inclusion criteria may apply, please refer to the protocol.
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 PR) after at least 2 prior systemic lines of therapy (including anti-
D20mAb and an alkylating agent). The treating physician should
discuss with the patient all available treatment options, including the
use of CAR-T cell therapy, evaluating benefits and risks before
considering enrolment in this study.
- 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 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.
- Patients must have received as prior therapies:
a) BTK inhibitor and
b) Anti-CD20 monoclonal antibody therapy
The treating physician should discuss with the patient all available
treatment options, including the use of CAR-T cell therapy, evaluating
benefits and risks before considering enrolment in this study.
- 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.
|
|
| E.4 | Principal 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 patient has been disease free for ≥ 2 years
- With the exception of alopecia, any unresolved non-haematological toxicities from prior therapy ≥ CTCAE Grade 2 at the time of starting study treatment
- Known medically apparent CNS lymphoma or leptomeningeal disease
- Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values at screening:
a) Absolute neutrophil count < 1.0 × 10^9/L; < 0.75 × 10^9/L in participants with known bone marrow involvement of malignant disease
b) Platelets < 75 × 10^9/L; < 50 × 10^9/L in participants with known bone marrow involvement of malignant disease
c) 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 OR Glycosylated haemoglobin ≥ 8.0% (63.9 mmol/mol)
- Prior treatment with any of the following:
a) 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
b) 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.
c) Prior allogenic 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, CAR-T therapy)
and/or autologous HSCT within 3 months from the first dose of
capivasertib.
d) Receipt of live, attenuated vaccine within 28 days before the first
dose of study treatment(s).
e) Patients who, due to other medical conditions /prior history
/concomitant medications are, in the investigator's opinion, at a risk of a
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.
- Patients who, in the Investigator's opinion, require immediate
cytoreductive therapy for disease control
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective response rate is defined as the proportion of patients achieving either complete response or partial response according to the Lugano 2014 Classification for NHL as assessed by blinded independent central review (BICR) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Assessment based on Lugano 2014 Classification:
Weeks 8, 16, 24, 36, 48, and 60 and thereafter every 24 weeks for FL/MZL and every 12 weeks for
MCL, or as clinically indicated until radiological progression of disease |
|
| E.5.2 | Secondary end point(s) |
1. 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
2. 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
3.Overall survival is defined as time from the date of first dose until the date of death due to any cause.
4. Patient-reported disease-related symptoms, functioning and 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)
5. Patient-reported symptomatic AEs and overall side effect burden as measured by PGI-TT and selected items from PRO CTCAE.
6. Time to first subsequent therapy or death (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
7. Time to objective response (TTR) is defined 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
8. Safety and tolerability will be evaluated in terms of AEs, vital signs, clinical laboratory and ECGs
9. Plasma concentration of capivasertib pre-dose and post-dose |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1, 2, 7: based on Lugano 2014 Class.: Weeks 8, 16, 24, 36, 48, 60 and thereafter every 24 w for FL/MZL and every 12 w for MCL, or as clinically indicated until radiological progression of disease
3. Patient survival is monitored throughout the study and in FU period
4. C1D1 and every 4 weeks from C1D1 for the first 24 w and then every 12 w thereafter until 12 w post progression
5. C1D1, every week from C1D1 for the first 4 weeks, every 4 weeks for the next 8 weeks, and every 12 weeks afterwards until EOT
6. Monitored during follow up period
8: AEs, vital signs, clinical laboratory: Every patient visit from screening until EOT; ECG: on screening, C1D1, C2D1, Pre-dose C3D1 and every 12 weeks thereafter or as clinically indicated
9: C1D1: post-dose; C1D8, 15, 22: pre-dose |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 10 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Denmark |
| France |
| Korea, Republic of |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study is defined as the last visit of the last patient in the study or last scheduled procedure shown in the Schedule of Activities in the relevant Module for the last patient in the study globally. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 8 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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