| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Relapsed/Refractory Peripheral T-Cell Lymphoma
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| E.1.1.1 | Medical condition in easily understood language |
| Relapsed/Refractory Peripheral T-Cell 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 | 10025310 |
| E.1.2 | Term | Lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 objective response rate (ORR) with valemetostat tosylate monotherapy treatment in R/R PTCL, including R/R ATL. Subjects with R/R ATL are to be enrolled in a separate cohort and will be analyzed independently.
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| E.2.2 | Secondary objectives of the trial |
- To evaluate the duration of response (DoR);
- To assess the CR rate;
- To evaluate the duration of CR (DoCR);
- To assess the PR rate;
- To assess the safety and tolerability of valemetostat tosylate monotherapy. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Sign and date the ICF, prior to the start of any study-specific qualification procedures.
2. Subjects ≥18 years of age or the minimum legal adult age (whichever is greater) at the time the ICF is signed.
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1, or 2
4. Cohort 1 (R/R PTCL): Should be pathologically confirmed by the local pathologist/investigators; local histological diagnosis will be used for eligibility determination. Subjects with the following subtypes of PTCL are eligible, according to 2016 World Health Organization classification prior to the initiation of study drug. Any T-cell lymphoid malignancies not listed below are excluded. Below is the complete list of eligible subtypes:
- Enteropathy-associated T-cell lymphoma
- Monomorphic epitheliotropic intestinal T-cell lymphoma
- Hepatosplenic T-cell lymphoma
- Primary cutaneous γδ T-cell lymphoma
- Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma
- PTCL, not otherwise specified
- Angioimmunoblastic T-cell lymphoma
- Follicular T-cell lymphoma
- Nodal PTCL with TFH phenotype
- Anaplastic large cell lymphoma, ALK positive
- Anaplastic large cell lymphoma, ALK negative
5. Cohort 2 (R/R ATL): (acute, lymphoma, or unfavorable chronic type). R/R ATL should be pathologically or hematocytologically confirmed by the local pathologist/investigators; local histological/ hematocytological diagnosis will be used for eligibility determination. The positivity of anti-HTLV-1 antibody will be locally determined for eligibility.
6. Must have at least 1 of the following lesions which are measurable in 2 perpendicular dimensions on CT (or MRI) based on local radiological read:
- Longest diameter (LDi) ≥2.0 cm for a nodal lesion
- LDi ≥1.0 cm for an extranodal lesion
For Cohort 2 (ATL), subjects who had disease only in peripheral blood and skin lesions are eligible, as defined below.
o An abnormal lymphocyte count (actual number) is ≥1.0 × 10^9 /L and the abnormal lymphocyte-to-leucocyte ratio is ≥5%.
o Skin lesion(s) measured by modified severity weighted assessment tool (mSWAT) score.
7. Documented refractory, relapsed, or progressive disease after at least 1 prior line of systemic therapy.
Refractory is defined as
• Failure to achieve CR (or uncertified CR [CRu] for ATL) after first-line therapy; or
• Failure to reach at least PR following second-line therapy or beyond.
8. Must have at least 1 prior line of systemic therapy for PTCL or ATL.
• Subjects must also be considered as HCT ineligible during Screening due to disease status (active disease), comorbidities, or other factors; the reason for HCT ineligibility must be clearly documented.
• In Cohort 1, subjects with ALCL must have prior brentuximab vedotin treatment.
Please refer to the protocol for the full list of inclusion criteria. Below are only the inclusion criteria that have been altered:
9. Local laboratory data must meet the following criteria at both Screening and prior to dosing on the planned Cycle 1 Day 1 Visit to confirm relatively preserved organ function:
13.If male with partner of childbearing potential, the subject must be surgically sterile or willing to use highly effective birth control (Section 10.3.6) upon enrollment, during the Treatment Period, and for 3 months following the last dose of study drug.
17.Estimated life expectancy >3 months based on investigator’s opinion.
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| E.4 | Principal exclusion criteria |
Unless otherwise specified, the below criteria will be evaluated and subjects who meet any of the following criteria will be disqualified from entering the study:
1. Diagnosis of mycosis fungoides, Sézary syndrome, and primary cutaneous ALCL and systemic dissemination of primary cutaneous ALCL
2. Diagnosis of precursor T-cell lymphoblastic leukemia and lymphoma (T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma), T-cell prolymphocytic leukemia, or T-cell large granular lymphocytic leukemia
3. Prior malignancy active within the previous 2 years except for locally curable cancer that is currently considered as cured, such as cutaneous basal or squamous cell carcinoma, superficial bladder cancer, or cervical carcinoma in situ, or an incidental histological finding of prostate cancer
4. Presence of active central nervous system (CNS) involvement of lymphoma
5. History of autologous HCT within 60 days prior to first dose of study drug
6. History of allogeneic HCT within 90 days prior to the first dose of study drug
7. Clinically significant graft-versus-host disease (GVHD) or GVHD requiring systemic immunosuppressive prophylaxis or treatment
8. Inadequate washout period from prior lymphoma-directed therapy before enrollment, defined as follows:
- Prior systemic therapy (eg, chemotherapy, immunomodulatory therapy, or monoclonal antibody therapy) within 3 weeks or 5 half-lives of the drug, whichever is longer, prior to the first dose of study drug
- Had curative radiation therapy or major surgery within 4 weeks or palliative radiation therapy within 2 weeks prior to the first dose of study drug
9. Uncontrolled or significant cardiovascular disease, including the following:
- Evidence of prolongation of QT/QTc interval (eg, repeated episodes of QT corrected for heart rate using Fridericia’s method [QTcF] >450 ms) (average of triplicate determinations)
- Diagnosed or suspected long QT syndrome, or known family history of long QT syndrome
- History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes
- Uncontrolled arrhythmia (subjects with asymptomatic, controllable atrial fibrillation may be enrolled), or asymptomatic persistent ventricular tachycardia
- Subject has clinically relevant bradycardia of ≤50 bpm unless the subject has a pacemaker
- History of second- or third-degree heart block. Candidates with a history of heart block may be eligible if they currently have pacemakers, and have no history of fainting or clinically relevant arrhythmia with pacemakers, within 6 months prior to Screening
- Myocardial infarction within 6 months prior to Screening
- Angioplasty or stent graft implantation within 6 months prior to Screening
- Uncontrolled angina pectoris within 6 months prior to Screening
- New York Heart Association (NYHA) Class 3 or 4 congestive heart failure
- Coronary/peripheral artery bypass graft within 6 months prior to Screening
- Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or diastolic blood pressure >110 mmHg)
- Complete left bundle branch block
10. History of treatment with other EZH inhibitors
11. Current use of moderate or strong cytochrome P450 (CYP)3A inducers (Table 10.4)
12. Systemic treatment with corticosteroids (>10 mg daily prednisone equivalents). Note: Short-course systemic corticosteroids (eg, prevention/treatment for transfusion reaction) or use for a non-cancer indication (eg, adrenal replacement) is permissible.
Please refer to the protocol for the full list of exclusion criteria. Below list only additional exclusion criteria points changed to limit character max:
14. Any positive test for hepatitis B virus or hepatitis C virus indicating acute or chronic infection within 28 days prior to the first dose of study drug (hepatitis B surface antigen positive or have detectable HBV DNA or detectable HCV RNA).
20. Known or suspected hypersensitivity to valemetostat tosylate or any of the excipients |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Cohort 1
ORR is defined as the proportion of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR), assessed by BICR, among subjects with centrally confirmed PTCL-eligible histology.
Cohort 2
ORR is defined as the proportion of subjects with a BOR of CR, uncertified CR (CRu), or PR, assessed by BICR, among subjects with centrally confirmed histology/peripheral blood assessment. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cohort 1: At least 10 months after the first dose of valemetostat tosylate of the last subject enrolled into Cohort 1
Cohort 2: At least 10 months after the first dose of valemetostat tosylate of the last subject enrolled into Cohort 2 |
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| E.5.2 | Secondary end point(s) |
- DoR is defined as the time from the date of the first documentation of objective response (CR, CRu [ATL only] or PR) to the date of the first documentation of disease progression (progressive or relapsed disease) based on BICR assessments or to death due to any cause, whichever occurs first.
- Complete response rate is the percentage of subjects achieving CR (and CRu, in Cohort 2) as the BOR based on BICR.
- DoCR, is defined as the time from the date of the first documentation of CR (also CRu, in Cohort 2) to the date of the first documentation of disease progression (progressive or relapsed disease) based on BICR assessments or to death due to any cause, whichever occurs
first.
- Partial response rate is the percentage of subjects achieving PR as the BOR based on BICR assessment.
- All safety assessments, including AE reporting (TEAEs; treatment-emergent adverse events of special interest [TEAESI]; treatment emergent serious adverse events [TESAEs]; TEAEs by severity [CTCAE grading, including Grade 3 and Grade 4]; fatal events; and TEAEs leading to treatment discontinuation, interruption, or reduction), laboratory assessments, vital signs and electrocardiogram (ECG) (including corrected QT interval [QTcF] by central ECG reading) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Cohort 1: At least 10 months after the first dose of the last subject enrolled into Cohort 1
Cohort 2: At least 10 months after the first dose of the last subject enrolled into Cohort 2
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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 | No |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| This study will include 2 cohorts |
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| 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 | 25 |
| 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 |
| Canada |
| Japan |
| Korea, Republic of |
| Taiwan |
| United States |
| France |
| Netherlands |
| Spain |
| Germany |
| Italy |
| United Kingdom |
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| 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
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The last subject’s last visit is defined as the completion of survival follow-up of at least 3 years after the first dose of the last subject either from Cohort 1 or Cohort 2, whichever occurs later.
The subject’s EOS is defined as the date of his/her last study visit/contact.
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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