E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Epstein-Barr Virus-Positive (EBV+) Relapsed/Refractory Lymphomas |
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E.1.1.1 | Medical condition in easily understood language |
Epstein-Barr Virus-Positive (EBV+) Relapsed/Refractory Lymphomas |
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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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10071441 |
E.1.2 | Term | Epstein-Barr virus associated 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 evaluate the anti-tumor activity of the combination treatment of nanatinostat (Nstat) with valganciclovir (VGCV) based on objective tumor response rates |
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E.2.2 | Secondary objectives of the trial |
To determine the duration of tumor control To determine survival outcomes To describe the safety profile of the combination treatment of Nstat with VGCV To generate pharmacokinetic (PK) data with the intended commercial dose and administration of Nstat
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Adult patients age ≥18 years at the time of informed consent. 2. Histologically confirmed (by 2016 WHO classification) EBV+ lymphoma* per local laboratory by EBER-ISH (or for PTLD only, by LMP-1 immunohistochemistry) on a representative disease specimen. Any degree of EBER-ISH or LMP-1 positivity is considered to be eligible (ie, there is no cut-off value for % positive cells). * Tumor cells are EBV+, with the exception of AITL, which is characterized by EBV-negative neoplastic T cells and EBV+ associated B-lineage cells (of immunoblastic/plasmablastic immunophenotype) a. A recent FFPE specimen must be available for central review. The specifications for the age of the tumor samples are: •For patients with ENKTL, AITL, PTLD and HIV-L: preferably ≤1 year old. For tumor specimens >1 year old, please consult the Medical Monitor to discuss eligibility. •For patients with all other lymphoma subtypes: preferably ≤6 months old. For tumor specimens >6 months old, please consult the Medical Monitor to discuss eligibility. 3. For ENKTL patients only: Relapsed or refractory* disease following 1 or more prior systemic therapies with a curative intent. Patients must have failed an asparaginase-containing regimen. 4. For non-ENKTL patients only: Relapsed or refractory* disease following 2 or more prior systemic therapies with a curative intent, with the following specifications: a. For EBV+ DLBCL, NOS: Patients must have received at least one course of an anti CD20 immunotherapy such as rituximab, and at least one course of anthracycline-based chemotherapy (unless contraindicated due to cardiac dysfunction, in which case, an accepted anthracycline-free alternative for DLBCL was given). b. For PTLD: Patients must have received immunotherapy with an anti-CD20 agent. c. For HL: Patients must have received at least one course of anthracycline-based chemotherapy (unless contraindicated due to cardiac dysfunction). *Patients are considered to have refractory disease if they had no response (ie, no CR or PR), or a response lasting <6 months to a prior systemic therapy. 5. Patients with the following lymphomas associated with HIV infection (HIV-L): plasmablastic, Burkitt, Hodgkin lymphoma and DLBCL. 6. Patients with HIV-L should meet defined criteria for inclusion 7. No available standard therapies in the opinion of the Investigator. 8. Not eligible for high-dose chemotherapy with allogeneic/autologous stem cell transplantation or CAR-T therapy at the time of study entry. 9. Presence of at least one bi-dimensionally measurable lesion by CT or MRI: longest diameter (LDi) >1.5 cm for a nodal lesion; LDi >1.0 cm for an extranodal lesion within 28 days prior to start of treatment. 10. Able to provide a core or excisional lymph node biopsy for biomarker analysis from an archival biopsy at screening. 11. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. 12. All acute toxic effects of any prior anti-tumor therapy resolved to Grade ≤1 before initiation of study treatment (excluding alopecia and stable Grade 2 sensory neuropathy). 13. Required baseline laboratory data (within 2 weeks prior to start of study drug administration) as shown in the protocol 14. Life expectancy >3 months. 15. Women of childbearing potential (ie, reached menarche, and not post-menopausal [(no menses for 12 months without an alternative medical cause) or surgically sterile]) must have the following: a. Understand that the study medication is expected to have teratogenic risk. b. Have a negative serum beta human-chorionic gonadotropin (β-hCG) pregnancy test at screening. c. Commit to continued abstinence from heterosexual intercourse (excluding periodic abstinence or the withdrawal method) or begin a highly effective method of birth control with a Pearl-Index <1%, without interruption, throughout the study dosing period and for 6 months after the last dose of nanatinostat. Apart from abstinence, highly effective methods of birth control include the following: I. Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal). ii. Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable). iii. Intrauterine device (IUD). iv. Intrauterine hormone-releasing system (IUS). v. Bilateral tubal occlusion. vi. Vasectomized partner. 16. Male patients must agree to use condoms during intercourse throughout the study dosing period and for 90 days after the last dose of nanatinostat. Female partners of male patients participating in the study are to consider the use of effective methods of contraception while their partner is treated on study and for 90 days after the last administration of nanatinostat. 17. The patient is willing and able to provide informed consent and comply with the protocol. |
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E.4 | Principal exclusion criteria |
1. Presence or history of central nervous system (CNS) involvement by lymphoma. 2. Systemic anticancer therapy within 21 days prior to Cycle 1 Day 1 dosing. 3. Antibody (anticancer) agents within 28 days of Cycle 1 Day 1 dosing. 4. Less than 14 days from prior local site radiation therapy. 5. Less than 60 days from prior autologous hematopoietic stem cell or solid organ transplant. 6. Less than 21 days from prior CAR-T therapy (any AEs must be grade 1 or less for enrollment). 7. Less than 90 days from prior allogeneic transplant. 8. Receiving systemic corticosteroids during the last week prior to Cycle 1 Day 1, unless administered at a dose equivalent to ≤20 mg/day of prednisone. 9. For recipients of prior allogeneic HSCT: Receiving systemic immunosuppressants as either prophylaxis or treatment for GVHD. 10. Major surgery within 28 days within the first dose of study drug. In case of recent major surgery, the patient must have recovered adequately from the procedure and/or any complications prior to starting study treatment. Note: Minor surgery (eg, minor biopsy of extracranial site, central venous catheter placement, shunt revision) is permitted within 3 weeks prior to enrollment. 11. Is currently participating in or has participated in an interventional study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. •Note: Individuals who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks since the last dose of the previous investigational agent. 12. History of previously treated cancer except for the following: a. Adequately treated: - local basal cell or squamous cell carcinoma of the skin, or related localized non melanoma skin cancer. - cervical carcinoma in situ. - superficial bladder cancer. - localized prostate cancer undergoing surveillance or previously fully resected. - localized breast cancer treated with surgery and/or radiotherapy and/or endocrine therapy, but not including systemic chemotherapy. - other adequately treated Stage 1 or 2 cancer currently in complete remission. 13. Inability to take oral medication, malabsorption syndrome or any other gastrointestinal condition (nausea, diarrhea, vomiting) that may impact the absorption of nanatinostat and valganciclovir. 14. Active graft-versus-host disease (GvHD). 15. Positive hepatitis B core antibody or surface antigen unless quantitative DNA polymerase chain reaction (PCR) is negative, and patient will be receiving prophylaxis for reactivation. 16. Positive hepatitis C virus on RNA PCR. 17. Known SARS-CoV-2 positivity. 18. History of allergic reactions attributed to compounds of similar chemical or biologic composition to valganciclovir or nanatinostat. 19. Active infection requiring systemic therapy (excluding viral upper respiratory tract infections). Patients may be receiving prophylactic antiviral, antifungal or antibacterial therapies at the discretion of the Investigator. 20. Prolongation of corrected QT interval using Fridericia’s formula (QTcF) to >480 msec, requires the coadministration of drugs known to prolong QT (Class Ia [disopyramide, quinidine, procainamide] and Class III [sotalol, dofetilide, ibutilide] antiarrhythmic agents), and/or has a history of Torsades de Pointes (TdP). 21. Receiving concomitant drugs that are inhibitors of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP; unless they can be held for 2 weeks or 5 half-lives, whichever is longer), prior to administration of nanatinostat. 22. Psychiatric illness/social situations/substance abuse disorder that would interfere with compliance with study requirements. 23. Has a prior or ongoing clinically significant illness, medical condition, physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the Investigator’s opinion, could affect the safety of the patient, impair the assessment of study results, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate. 24. Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the Screening visit through 6 months after the last dose of nanatinostat.
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E.5 End points |
E.5.1 | Primary end point(s) |
• Objective response rate (ORR) as assessed by an Independent Review Committee (IRC) – defined as the proportion of patients who achieve a complete response (CR) or partial response (PR) using the 2007 International Working Group (IWG) criteria.
The Investigator will also use the 2007 IWG criteria for assessment of progression/relapse and for any clinical decisions requiring assessment of disease progression/relapse.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary efficacy endpoint is ORR assessed by an IRC. Disease response assessments will be made every 8 weeks until 24 weeks, and then every 12 weeks for the remainder of the study, according to the revised response criteria for malignant lymphoma based on the IWG-NHL guidelines. PET/CT scans (or MRI if a CT with contrast is contraindicated) will be performed at baseline, and for the 8-week and 16-week tumor assessments only [for combination therapy]. Subsequent evaluations will be by CT with contrast (without PET) or MRI only. Efficacy will be evaluated in terms of ORR, DOR, PFS, OS, TTP, and TTNT. ORR will be used to move from Stage 1 to Stage 2.
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E.5.2 | Secondary end point(s) |
• Duration of response (DOR) – defined as the interval from the date of first observed CR or PR to the date of disease progression, death due to any cause, or last adequate (radiographic) response assessment. • Time to next anti-lymphoma treatment (TTNLT) – defined as the interval from the start of study drug treatment to date of next anti-lymphoma treatment. • Progression-free survival (PFS) – defined as the interval from the start of study drug treatment to the date of first documented disease progression or death from any cause, whichever occurs first. • Time to progression (TTP) – defined as the interval from the start of study drug treatment to date of disease progression. • Overall survival (OS) – defined as the interval from the start of study drug treatment to date of death, for any reason. • Incidence and severity of treatment-emergent adverse events (TEAEs). Adverse events will be graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. • Pharmacokinetic (PK) parameters (eg, time to maximum plasma concentration [tmax], maximum plasma concentration [Cmax], area under the plasma concentration-time curve [AUC]).
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall survival,Time to next anti-lymphoma treatment, Duration of response, Progression free survival |
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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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 8 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
Korea, Republic of |
Singapore |
Taiwan |
United States |
France |
Germany |
Italy |
United Kingdom |
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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
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The end of the study occurs when all patients have either progressed, discontinued, died, become lost to follow-up, or have maintained a CR, PR, or SD for at least 3 years, or when the trial is terminated by the Sponsor.
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |