E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed/refractory mantle cell lymphoma. |
|
E.1.1.1 | Medical condition in easily understood language |
Relapsed/refractory mantle cell lymphoma. |
|
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 | HLT |
E.1.2 | Classification code | 10026798 |
E.1.2 | Term | Mantle cell lymphomas |
E.1.2 | System Organ Class | 100000004851 |
|
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 |
The primary objective is to assess the overall response rate (ORR) at 6 months with lenalidomide-venetoclax and rituximab, in patients with relapsed or refractory mantle cell lymphoma, by use of an MRD driven strategy. |
|
E.2.2 | Secondary objectives of the trial |
To evaluate, at 24 months:
1. ORR in untreated patients, not candidates for chemotherapy
2. ORR in patients previously treated with ibrutinib
3. ORR in patients with TP53-mutation and/or 17p deletion
4. Progression-free survival (median)
5. Response duration (median)
6. Molecular remission rate by PCR according to EURO-MRD guidelines
7. MRD vs PET-CT for correlation with PFS/OS
8. Overall survival (median)
9. Safety (Grade 3-4 AE according to CTC v 4.03)
10. Health-related quality of Life assessment
11. Evaluation of biomarkers for efficacy, by mutational profile and immunohistochemistry
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Age >18 years
2. Histologically confirmed (according to the WHO 2016 classification) mantle cell lymphoma stage I-IV
3.
a. Who have received at least 1 prior rituximab-containing chemotherapy regimen, with documented relapse or disease progression following
the last anti-MCL treatment
OR
b. Are not considered to be candidates for chemotherapy due to frailty or comorbidity
4. At least 1 measurable site of disease (>1.5 cm long axis)
5. WHO performance status 0 – 3
6. Written informed consent.
7. Female subjects of childbearing potential must (see page 52 for definition of not fertile):
a. Understand that the study medication is expected to be teratogenic
b. Agree to use, and be able to comply with, highly effective contraception without interruption, 4 weeks before starting study drug,
throughout study drug therapy (including dose interruptions) and for 4 weeks after the end of study drug therapy, even if she has
amenorrhoea.
c. All fertile women must agree to perform monthly pregnancy tests while on study medication and until 4 weeks after completion of study
drug. Tests must have a minimum sensitivity of 25 mIE/ml and be medically witnessed
d. Highly effective contraception include:
e. Implant*
f. Levonorgestrel-releasing intrauterine system (IUS)*
g. Medroxyprogesterone acetate depot
h. Tubal sterilisation
i. Sexual intercourse with a vasectomised male partner only; vasectomy must be confirmed by two negative semen analyses
j. Ovulation inhibitory progesterone-only pills (i.e., desogestrel)
NB! Patients using a hormonal method, must also use a second barrier method.
k. Sexual abstinence (if refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The
reliability of sexual abstinence needs to be evaluated in relation to the preferred and usual lifestyle of the subject).
8. Male subjects must
a. Agree to use condoms throughout study drug therapy, during any dose interruption and for one week after cessation of study therapy if
their partner is of childbearing potential and has no contraception.
b. Agree not to donate semen during study drug therapy and for one week after end of study drug therapy.
9. All subjects must
a. Agree to abstain from donating blood while taking study drug therapy and for one week following discontinuation of study drug therapy.
b. Agree not to share study medication with another person and to return all unused study drug to the investigator
|
|
E.4 | Principal exclusion criteria |
1.
a. Chemotherapy or radiotherapy within 3 weeks
b. Therapeutic antibodies or BTK inhibitors within 4 weeks
c. Radioimmunotherapy within 10 weeks
d. Major surgery within 4 weeks of inclusion in this trial.
2. Previous treatment with venetoclax
3. Impaired liver function: AST and ALT >3.0 × the upper normal limit (ULN) of institution's normal range; Bilirubin > 1.5 × ULN. Subjects with
Gilbert's Syndrome may have a bilirubin > 1.5 × ULN, per discussion between the investigator and medical monitor. Elevated Bilirubin due
to haemolytic anemia or caused by lymphoma, is not an exclusion criterion.
4. Absolute neutrophil count (ANC) <1.0x 109, unless caused by bone marrow infiltration by lymphoma.
5. Platelet count <60 x 109, unless caused by bone marrow infiltration by lymphoma.
6. Creatinine clearance below 50 ml/min (Cockcroft-Gault)
7. Known CNS lymphoma.
8. Heart failure in NYHA stage IV or other serious CVD
9. Pulmonary failure (ex chronic disease with hypoxemia)
10. Active serious infections such as hepatitis B or C and HIV
11. Conditions with serious immunocompromised state
12. Breastfeeding women must be excluded or stop breastfeeding
13. Other active malignancy.
14. Psychiatric illness or condition which could interfere with the subjects’ ability to understand the requirements of the study.
15. Requirement of corticosteroid therapy at a dose >10 mg prednisolone/day.
16. Hypersensitivity to venetoclax, lenalidomide or rituximab, or HACA against rituximab.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable is the evaluation of overall response rate (ORR) at 6 months with lenalidomide-venetoclax and rituximab, in patients with relapsed or refractory mantle cell lymphoma (MCL), using an MRD driven strategy. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 6 months of treatment. |
|
E.5.2 | Secondary end point(s) |
1. ORR in untreated patients, not candidates for chemotherapy
2. ORR in patients previously treated with ibrutinib
3. ORR in patients with TP53-mutation and/or 17p deletion
4. Progression-free survival
5. Response duration
6. Molecular remission rate by PCR according to EURO-MRD guidelines
7. Overall survival
8. Safety
9. Evaluation of biomarkers for efficacy, by mutational profile and immunohistochemistry
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Continously during treatment. |
|
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 | 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 | 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 | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 5 |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |