| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Follicular lymphoma (FL) or Marginal Zone Lymphoma (MZL) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Follicular lymphoma is a type of blood cancer. It is the most common of the indolent (slow-growing) non-Hodgkin's lymphomas, and the second-most-common form of non-Hodgkin's lymphomas overall. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10029473 |
| E.1.2 | Term | Nodular (follicular) 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.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the objective response rate (ORR) of ME-401 in relapsed or refractory FL or MZL, based on the Modified Lugano Response Criteria (Appendix 5), and determined by an Independent Response Review Committee (IRRC) |
|
| E.2.2 | Secondary objectives of the trial |
1. To evaluate the efficacy of ME-401 as assessed by an IRRC:
o Duration of response (DOR)
o Complete response (CR) rate
o Progression-free survival (PFS)
o Time to treatment failure (TTF)
o Recapture of response
o Duration of recaptured response (DORR)
2. To evaluate the efficacy of ME-401 as assessed by the Investigator:
o Objective response rate (ORR)
o Duration of response (DOR)
o Complete response (CR) rate
o Progression-free survival (PFS)
o Time to treatment failure (TTF)
o Recapture of response
o Duration of recaptured response (DORR)
3. To evaluate the overall survival (OS)
4.To evaluate the safety profile of ME-401
o Overall incidence of treatment-emergent adverse events (TEAEs)
o Incidence of adverse events of special interest (AESIs)
o Time to occurrence of AESIs
5.To evaluate the PK of ME-401 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent.
2. Age ≥18 years (or age of majority).
3. Histologically confirmed diagnosis as defined in the World Health
Organization (WHO) classification (Swerdlow 2016) of:
a. Follicular lymphoma (FL) limited to Grade 1, 2, or 3a; or
b. Marginal zone lymphoma (MZL), including nodal, extranodal, and
splenic MZL (histopathological report confirming diagnosis must be
available during screening procedures).
4. Subjects with relapsed or refractory FL or MZL who received ≥2 prior therapy regimens. A previous regimen is defined as one of the following:
at least two months of single-agent therapy or at least two consecutive cycles of polychemotherapy, autologous transplant, or
radioimmunotherapy. Prior therapy must include an anti-CD20
monoclonal antibody (mAb) and an alkylating agent(s). Relapsed or
refractory disease is defined as:
a. Relapsed disease: disease progression after a response (CR or PR)
lasting ≥ 6 months
b. Refractory disease: no response to therapy (no CR or PR), or response lasting <6 months
5. At least one bi-dimensionally measurable nodal lesion >1.5 cm or
extranodal lesions >1 cm in its longest diameter by computed
tomography (CT) scan as defined by the Modified Lugano
Classification(Appendix 5).
a. Previously irradiated lesions can be selected as target lesions only in cases of unequivocal evidence of progression.
b. For subjects with splenic MZL only: diffuse spleen involvement with splenomegaly, which is defined as the splenic vertical length greater than 13 cm.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 (Oken 1982; Appendix 6).
7. Adequate hematologic parameters at screening unless abnormal
values are due to lymphoma per Investigator assessment:
a. Absolute neutrophil count (ANC) ≥1.0 × 109/L (≥ 1,000/mm3)
b. Platelet count ≥75.0 × 109/L (≥ 75,000/mm3)
8. Adequate renal and hepatic function per local laboratory reference
range at screening as follows:
a. Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic
transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamicpyruvate transaminase (SGPT) ≤3.0 × upper limit of normal(ULN)
b. Total bilirubin ≤2.0 × ULN or ≤3 × ULN for subjects with Gilbert's
syndrome
c. Serum creatinine ≤1.5 × ULN or estimated glomerular filtration rate
(eGFR) >50 mL/min using the Cockcroft-Gault equation (Appendix 2)
9. QT-interval corrected according to Fridericia's formula (QTcF) ≤450
milliseconds (msec); subjects with QTc >450 msec but <480 msec may
be enrolled provided the QTc prolongation is due to a right bundle
branch block (RBBB), left bundle branch block (LBBB), or pacemaker and is confirmed stable by a cardiologist.
10. Left ventricular ejection fraction (LVEF) ≥ 45% as measured by
echocardiogram or multigated acquisition scan (MUGA). If LVEF <45%
by ECHO, a repeat measurement can be conducted within the screening period.
11. Subjects must have completed any prior systemic anti-cancer
treatment within ≥4 weeks of Cycle 1 Day 1 (or ≥5 times the half-life
[t½], whichever is longer); ≥8 weeks for antibody agents; ≥2 weeks for radiation therapy; and ≥3 months for high dose therapy with stem cell transplantation or CAR T cell therapy or radioimmunotherapy.
12. All adverse events and laboratory toxicities related to prior therapy must resolve to Grade ≤1 prior to the start of the study therapy (unless otherwise specified in eligibility criteria).
13. For females of childbearing potential, a negative serum human
chorionic gonadotropin (hCG)pregnancy test within 28 days of study Day 1 and negative hCG result on study Day 1.
14. Subjects must agree to use appropriate contraception methods
during the clinical study (Appendix 4).
15. Subject is willing and able to comply with all scheduled visits,
treatment plans, laboratory tests, and other study procedures. |
|
| E.4 | Principal exclusion criteria |
1. Histologically confirmed FL Grade 3b, or transformed disease
(assessed by the Investigator):
a. For patients with clinical (e.g., marked B-symptoms), laboratory (e.g., high lactate dehydrogenase [LDH]) or radiographic (e.g., high
standardized uptake value by positron emission tomography [PET])
signs of rapid disease progression, a fresh tumor biopsy prior to
enrollment is required to rule out transformed disease
2. Known lymphomatous involvement of the central nervous system.
3. Major surgical procedure within 4 weeks prior to study Day 1 (minor surgical procedures, [e.g., lymph node biopsy] performed within 1 day or with an overnight stay are allowed).
4. Prior therapy with PI3K inhibitors.
5. Any uncontrolled clinically significant illness including, but not limited to, active infections requiring systemic antimicrobial therapy,
hypertension, angina, arrhythmias, pulmonary disease, or autoimmune dysfunction.
6. Subjects who have tested positive for hepatitis B surface antigen
and/or hepatitis B core antibody plus have a positive hepatitis B
polymerase chain reaction (PCR) assay; subjects who have previously
tested positive with a negative PCR assay are permitted with appropriate anti-viral prophylaxis.
7. Positive hepatitis C virus antibody (HCV Ab); subjects with positive
HCV Ab are eligible if they are negative for HCV by PCR.
8. Known history of, or active human immunodeficiency virus (HIV)
infection.
9. Ongoing or history of drug-induced pneumonitis.
10. Previous or concurrent cancer that is distinct in primary site or
histology from indolent B-cell NHL within 3 years before start of study
treatment except for curatively treated cervical cancer in situ, nonmelanoma skin cancer, superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ], and T1 [tumor invades lamina propria]), and asymptomatic localized prostate cancer with no requirement for systemic therapy (or requiring only hormonal therapy) and with normal prostate-specific antigen values within ≥12 months prior to enrollment.
11. History of clinically significant cardiovascular abnormalities such as congestive heart failure (New York Heart Association classification ≥ II [NYHA 1994]), myocardial infarction within 6 months of study entry.
12. History of clinically significant gastrointestinal (GI) conditions,
particularly:
a. Known GI condition that would interfere with swallowing or the oral absorption or tolerance of study drug
b. Pre-existing malabsorption syndrome or other clinical situation that would affect oral absorption
13. Females who are pregnant; females who plan to breastfeed during study treatment through 90 days after ending treatment.
14. Psychiatric illness/social situations that would interfere with study
compliance.
15. Hypersensitivity or other clinically significant reaction to the study drug or its inactive ingredients.
16. Any other condition for which, in the opinion of the Investigator,
participation would not be in the best interest of the subject. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy endpoint is ORR, as determined by the IRRC,
defined as the proportion of subjects achieving the best response rating
of CR or PR based on the Modified Lugano Classification. ORR will be also be assessed by the Investigator as a secondary endpoint |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis for FL will be triggered after all 120 subjects in the
ITT IS FL Population enrolled in the study (except those who discontinue
early) have been followed for at least 6 months from the start of study
drug.
The primary analysis for MZL will be triggered after all 60 MZL subjects
enrolled in the study (except those who discontinue early) have been
followed for at least 6 months from the start of study drug |
|
| E.5.2 | Secondary end point(s) |
1. Duration of Response (DOR) and Duration of Recaptured Response
(DORR)
Duration of response (DOR) will be evaluated as a secondary endpoint and is defined as the time from documentation of the first CR or PR to the time of first disease progression based on the Modified Lugano Response Criteria. To evaluate the duration of response for subjects who had recapture of response on the CS dosing, duration of recaptured response (DORR) is defined as the time from recapture of response to the time of second disease progression. These endpoints will be assessed by the IRRC and Investigator independently
2. Progression-free survival (PFS)
Progression-free survival (PFS) will be assessed as a secondary endpoint and is defined as the time from initiation of treatment (Day 1) until first disease progression or death from any cause. Disease progression criteria are defined per Modified Lugano Response Criteria and will be assessed by the IRRC and Investigator independently.
3. Time to treatment Failure (TTF)
Time to treatment failure will be assessed as a secondary endpoint and is defined as the time from first dose of study drug to treatment failure. Treatment failure is defined as any treatment discontinuation due to disease progression, toxicity, or death.
4. Recapture of Response
Recapture of response is defined as achieving a second documented CR or PR after experiencing the first PD. Recapture of response rate will be assessed by the IRRC and Investigator independently as a secondary endpoint, and is defined as the proportion of subjects who achieved a CR or PR followed by a PD during IS dosing and subsequently switched to CS dosing and achieved a second documented CR or PR. Time to recapture of response will be assessed as a secondary endpoint, and is defined as the time from the first PD until the second documented CR or PR.
5. Overall Survival (OS)
OS will be assessed as a secondary endpoint and is defined as the time from initiation of treatment (Day 1) until death from any cause
independently from the study period or dosing schedule. OS time will be censored at the last date the subject is known to be alive when the confirmation of death is absent or unknown. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The primary analysis for FL will be triggered after all 120 subjects in the
ITT IS FL Population enrolled in the study (except those who discontinue
early) have been followed for at least 6 months from the start of study
drug.
The primary analysis for MZL will be triggered after all 60 MZL subjects
enrolled in the study (except those who discontinue early) have been
followed for at least 6 months from the start of study drug |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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.8.3 |
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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 59 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| New Zealand |
| Poland |
| Spain |
| Switzerland |
| Taiwan |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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