| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
| A rare type of non-hodgkin lymphoma |
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| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10058728 |
| E.1.2 | Term | Richter's syndrome |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 | 10058728 |
| E.1.2 | Term | Richter's syndrome |
| 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 | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1A) Randomised Question (main randomised component of the trial):
To compare the rate of progression free survival (PFS)* of participants with Richter's Syndrome (RS) who are given CHOP-R alone (chemo-immunotherapy, standard of care) against participants with RS who are given CHOP-R plus acalabrutinib (the investigational drug).
1B)Platform Study Questions:
Cohort 1: to assess the overall response rate (ORR)** at 6 months of participants who take acalabrutinib alone after relapse with RS or if their disease progressed whilst or after having CHOP-R therapy.
Cohort 2: to assess the overall response rate (ORR) of participants after 6 cycles of CHOP-R plus acalabrutinib.
*PFS - the length of time during and after the treatment that a patient lives with the disease but it does not get worse
**ORR - how well the participant's disease responds to treatment e.g. reaching partial or complete remission |
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| E.2.2 | Secondary objectives of the trial |
To evaluate:
2a) Overall survival (OS) - how long each of the participants live from day one of the trial.
2b) Randomised question only: overall response rate (ORR) - how many of the participants achieve (for example) a partial or complete remission at the end of CHOP-R treatment.
2c) Cohorts 1 and 2: Progression free survival (PFS)- the length of time during and after the extension study acalabrutinib treatment that the patient lives with the disease but it doesn't get worse.
2d) Quality of Life (QoL) assessed using the Eastern Cooperative Oncology Group (ECOG) performance status and the CLL17 and NHL-HG29 questionnaires - this is an assessment of the participants' general well-being and ability to carry out activities in their daily life.
2e) Toxicity - the types, severity, and frequency of side effects that the participants might have while on the trial.
2f) Proportion of patients proceeding to stem cell transplantation - the number of patients who reach a point where they can |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Inclusion criteria for the Randomised Trial
-Suitable for anthracycline-containing chemo-immunotherapy.
-Patients with CLL and newly diagnosed biopsy proven DLBCL-type RS.
-ECOG performance status of 0, 1, 2 or 3.
-Age 16 years and over.
-Signed written informed consent prior to performing any study-specific procedures
Inclusion criteria Cohort 1 (progressive RS following chemo-immunotherapy)
-Patients with relapsed/refractory RS who received anthracycline based chemotherapy with anti-CD20 monoclonal antibody.
-ECOG performance status of 0, 1, 2 or 3.
-Age 16 years and over.
-Signed written informed consent prior to performing any study-specific procedures
Inclusion criteria Cohort 2 (anthracycline-naïve RS patients, diagnosed while on ibrutinib)
-Ibrutinib-exposed CLL patients who have developed biopsy-proven DLBCL-type RS within four weeks of last dose of ibrutinib.
-No previous anthracycline treatment and suitable for anthracycline-containing chemo-immunotherapy.
-Patients with CLL and newly diagnosed biopsy proven DLBCL-type RS.
-ECOG performance status of 0, 1, 2 or 3.
-Age 16 years and over.
-Signed written informed consent prior to performing any study-specific procedures
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| E.4 | Principal exclusion criteria |
Exclusion criteria ALL
-Known central nervous system (CNS) involvement of CLL or DLBCL.
-Any other active malignancy that requires active treatment, with the exception of basal cell carcinoma, in-situ cervical cancer, and non-invasive squamous cell carcinoma of the skin.
-Chronic or ongoing active infectious disease
-Positive serology for Hepatitis B (HBKnown human immunodeficiency virus (HIV) positive.
-Patients with active bleeding or history of bleeding diathesis (e.g. haemophilia, von Willebrand disease).
-Patients receiving therapeutic anticoagulation with warfarin or equivalent (e.g. phenoprocoumon).
-Uncorrected prolonged prothrombin time (PT) or an activated partial thromboplastin time (APTT) > 2 x the upper limit of normal (ULN).
-Major surgery within 30 days prior to randomisation and/or inadequate recovery from any prior major surgery, toxicity or complications.
-Patients with malabsorption syndrome or medical conditions significantly affecting gastrointestinal function.
-Clinically significant cardiac disease including unstable angina, uncontrolled congestive heart failure, and unstable arrhythmias requiring therapy, with the exception of extra systoles or minor conduction abnormalities.
-Significant concurrent, uncontrolled severe medical condition including, but not limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease.
-History of significant cerebrovascular disease in the 6 months prior to randomisation, including intracranial haemorrhage.
-Known or suspected hypersensitivity to components of the investigational products
-Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to proposed start of treatment
-Current participation in any other interventional clinical study.
-Patients known or suspected of not being able to comply with a study
-Breast feeding women or women with a positive pregnancy test at screening.
-Women of childbearing potential and men not willing to use highly effective contraception during study and for 12 months after last dose of study therapy
Additional exclusion criteria for the Randomised Trial
-Prior therapy with CHOP or any anthracycline containing treatment at any time prior to randomisation.
-Ibrutinib-exposed CLL patients who have been newly diagnosed with RS within four weeks of their last dose of ibrutinib. (Ibrutinib-exposed CLL patients who discontinue ibrutinib due to toxicity or progressive CLL and later (more than four weeks) develop RS are not excluded from the randomised trial component).
-Previous acalabrutinib exposure.
Additional exclusion criteria for Cohort 1 (progressive RS following chemo-immunotherapy)
-Previous acalabrutinib exposure.
Additional exclusion criteria for Cohort 2 (anthracycline-naïve RS patients, diagnosed while on ibrutinib)
-Prior therapy with CHOP or any anthracycline containing treatment at any time prior to randomisation.
-Previous acalabrutinib exposure. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Randomised component:
Progression free survival (PFS) defined as the time from randomisation to the date of progression or death from any cause. Progression will be defined by the modified Cheson criteria. Patients who are alive and progression free at the time of analysis will be censored at date last seen. Any participants who withdraw or are lost to follow-up will also be censored at date last seen.
Single-arm Cohort 1 (progressive RS following chemo-immunotherapy):
Overall response after 24 weeks of treatment based on the modified Cheson criteria. Complete response (CR) and partial response (PR) are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the 6 month assessment or do not have the 6 month assessment will be considered non-responders.
Single-arm Cohort 2 (anthracycline-naïve RS patients, diagnosed while on ibrutinib):
Overall response after 6 cycles of treatment, defined by the modified Cheson criteria. CR and PR are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the post-cycle-6 assessment or do not have the post-cycle-6 assessment will be considered non-responders.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Randomised component: 2 years
Single-arm Cohort 1: 24 weeks
Single-arm Cohort 2: 6 cycles of CHOP-R (18 weeks) |
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| E.5.2 | Secondary end point(s) |
(1) Overall survival (OS) defined as time from date of randomisation (for randomised trial) or registration (to the relevant cohort for single-arm cohorts) to date of death from any cause. Participants who are alive at the time of analysis will be censored at date last seen. (Note that participants randomised to receive CHOP-R, who progress on the standard of care arm and are eligible for cohort 1, may enter single-arm Cohort 1 to receive acalabrutinib monotherapy. Their survival time for analysis of the randomised component will be from date of randomisation, and that used for analysis of Cohort 1 will be from date of registration to Cohort 1.)
(2) Overall response (ORR) (randomised component only) after cycle 6, defined by the modified Cheson criteria (Appendix 1). CR and PR are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the post-cycle-6 assessment or do not have the post-cycle-6 assessment will be considered non-responders.
(3) Overall response (cohort 1 only) after 12 weeks, defined by the modified Cheson criteria (Appendix 1). CR and PR are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the 12-week assessment or do not have the 12-week assessment will be considered non-responders.
(4) Progression free survival (PFS) (single-arm cohorts only) defined as the time from date of registration to date of progression or death from any cause. Progression will be defined by the modified Cheson criteria (Appendix 1). Participants who are alive and progression free at the time of analysis will be censored at date last seen. Any patients who withdraw or are lost to follow-up will also be censored at date last seen.
(5) Quality of Life (QoL), (assessed using ECOG performance status), and the CLL17 and NHL-HG29 questionnaires (Appendix 2)) at the end of cycles 4 and 6 for participants receiving CHOP-R as part of their treatment (randomised cohorts and Cohort 2), and at 12 and 24 weeks for participants receiving acalabrutinib monotherapy (Cohort 1).
(6) Toxicity defined as the number of participants who experience one or more adverse event grade 3 or higher or serious adverse event of any grade.
(7) Proportion of participants proceeding to allogeneic or autologous stem cell transplantation
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
(1) OS (all cohorts): 2 years
(2) ORR randomised component: 6 cycles of CHOP-R (18-weeks)
(3) ORR Cohort 1: 12 weeks
(4) PFS (cohorts 1 and 2): 2 years
(5) QoL randomised cohorts and Cohort 2: end of cycles 4 (12 weeks) and 6 (18 weeks); Cohort 1: 12 and 24 weeks
(6) Toxicity (all cohorts): 2 years
(7) Toxicity (all cohorts): 2 years |
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| 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 | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 |
| Platform arms are registration only. |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 16 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| 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
|
LPLV last patient, last visit.
The Trials Office will notify the MHRA and main REC that the trial has ended at the appropriate time and will provide them with a summary of the clinical trial report within 12 months of the end of trial. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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