| 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 |
|
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066481 |
| E.1.2 | Term | Hematological malignancy |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Phase I: To characterize safety and tolerability and determine the MTD and/or RP2D of MAK683
Phase II: To assess the anti-tumor activity of MAK683
|
| - |
|
| E.2.2 | Secondary objectives of the trial |
Phase I:
¿To characterize the anti-tumor activity of MAK683
¿To characterize the PK profile of MAK683
¿To characterize the pharmacodynamics effect of MAK683
Phase II:
¿To characterize the anti-tumor activity of MAK683
¿To characterize the safety and tolerability of MAK683
¿To characterize the PK profile of MAK683
¿To characterize the pharmacodynamics effect of MAK683
|
| - |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent must be obtained prior to any screening procedures
2. Age = 18 years
3. ECOG performance status 0 to 2
4. Patients have progressed after standard therapy or are intolerant of standard therapy and for whom no standard therapy exists.
5. Measurable disease according to RECIST v1.1 for patients with solid tumors or Cheson criteria for patients with NHL (Cheson et al 2014).
6. Tumor biopsy is mandatory at study entry. Patients must have a site of disease amenable for biopsy and be a candidate for tumor biopsy. On-Treatment biopsy is required for patients with solid tumors, unless determined by the Investigator as not clinically feasible.
7. Histologically or cytologically confirmed diagnosis is required for all indications
8. For patients with DLBCL and FL:
- In Phase II, patients are required to have documentation of EZH2 mutational status.
9. Patients with relapsed or refractory indolent lymphomas, such as FL, must have signs or symptoms indicating the necessity of therapy such as described in practice guidelines ( e.g. Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria, The British National Lymphoma Investigation (BNLI), Italian Society of Hematology (SIE) guideline, or others local practice guidelines).
10. For patients with NPC:
- Patients must have documentation of presence of p16/CDKN2A gene (at least one copy of p16/CDKN2A gene)
11. For patients with ovarian cancer:
- Patients must have primary tumor with great than 50% clear cell histomorphology.
12. For patients with prostate cancer:
- Patients must have evidence of castration resistance as evidenced by a confirmed rising PSA (per Prostate Cancer Working Group 2 [PCWG2] criteria) and a castrate serum testosterone level (i.e. = 50 ng/dL).
13. For patients with sarcoma:
- Enrollment is limited to epithelioid sarcoma, other types of sarcoma with SWI/SNF alterations may be considered with approval from Novartis. |
| - |
|
| E.4 | Principal exclusion criteria |
1. Other malignant disease than the one being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 3 years prior to study entry; completely resected basal cell and squamous cell skin cancers; completely resected carcinoma in situ of any type.
2. Symptomatic CNS involvement which are neurologically unstable or require increasing doses of steroids to control.
3. Impaired cardiac function or clinically significant cardiac disease.
4. Current active infection (e.g. viral, bacterial or fungal) requiring systemic therapy.
5. Severe and/or uncontrolled medical conditions that in the investigator’s opinion could affect the safety of individual or impair the assessment of study result.
6. B-cell lymphoma patients who have received prior allogeneic stem cell transplant
7. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal conditions (e.g. atrophic gastritis, peptic ulcer) that might impair the bioavailability of MAK683.
8. Patients with refractory/uncontrolled ascites or pleural effusion.
9. Major surgical procedure within 28 days prior to study treatment.
10. Patients who have received anti-cancer therapies within the following time frames prior to
the first dose of study treatment:
¿ B cell lymphoma patients who received autologous stem cell transplantation within 12
weeks prior to study drug
¿ Castration-Resistant prostate cancer patients who had received radiopharmaceutical agents or immunotherapy (e.g. sipuleucel-T) within 12 weeks prior to study drug
¿ The last dose of conventional cytotoxic chemotherapy: = 4 weeks (= 6 weeks for nitrosoureas and mitomycin-C)
¿ Biologic therapy (e.g., antibodies, CAR-T): = 4 weeks
¿ Non-cytotoxic small molecule therapeutics : = 5 half-lives
11. Any unresolved toxicity NCI CTCAE Grade = 2 from previous anticancer therapy with the exception of alopecia and vitiligo
12. Insufficient bone marrow function at screening:
a) Platelets = 50 x 109/L (50,000/mm3)
b) Hemoglobin (Hgb) = 80 g/L (8 g/dL)
c) Absolute neutrophil count (ANC) = 1.0 x 109/L (1000/mm3)
13. Insufficient hepatic and renal function at screening:
a) Alkaline phosphatase (in the absence of bone disease), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) more than or equal to 3 x ULN (more than or equal to 5 x ULN if subject has liver metastases)
b) Total bilirubin > 1.5 x ULN.
c) Serum creatinine > 1.5 x ULN and/or creatinine clearance = 50 mL/min (calculated
using Cockcroft-Gault formula
14. Concomitant use of the drugs/remedies that may cause pharmacokinetic drug-drug interactions.
15. Chronic steroid therapy other than following: Daily use 10 mg prednisone (or equivalent)
or lower dose steroid for control of nausea, vomiting, active autoimmune disease, and
seasonal allergies, or to prevent adrenocortical insufficiency. NOTE: topical steroid, or inhaled steroid use is permitted.
16. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
17. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 4 weeks after discontinuation of treatment.
18. Sexually active males unless they use a condom during intercourse while taking drug and
for 5 compound half-lives (2 days) plus 90 days after stopping study drug and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. |
| - |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I:
Safety:
1.Incidence of dose limiting toxicities (DLTs) in the first 28 days of treatment
2.Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital signs and ECGs
Tolerability:
Dose interruptions, reductions and dose intensity
Phase II:
Overall response rate (ORR), based on local assessment per Response Assessment of Hodgkin and Non-Hodgkin Lymphoma (Cheson, 2014),
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and PCWG2 |
Fase I:
Sicurezza d’impiego:
• Incidenza e natura delle tossicità limitanti la dose (DLT) nei primi 28 giorni di trattamento
• Incidenza e gravità degli eventi avversi e degli eventi avversi seri, comprese le alterazioni dei parametri di laboratorio, dei segni vitali e degli elettrocardiogrammi (ECG)
Tollerabilità:
• Interruzioni della dose, riduzioni della dose e intensità della dose
Fase II:
Valutazione tumorale in base a diversi criteri di risposta:
• DLBCL e altri linfomi a cellule B: Valutazione del linfoma di Hodgkin e del linfoma non-Hodgkin (Cheson et al 2014)
• Tumori solidi (diversi dal carcinoma della prostata): Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• Carcinoma della prostata: RECIST V1.1e Prostate Cancer Clinical Trials Working Group 2 (PCGW2) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I:
Safety:
1. Day 28
2. End of study
Phase II: End of study |
Fase I:
Sicurezza d’impiego:
1. Giorno 28
2. A fine studio
Fase II: A fine studio |
|
| E.5.2 | Secondary end point(s) |
Phase I part:
ORR, Duration of overall response (DOR), Progression-free survival (PFS) and Best Overall Response (BOR)
Plasma concentrations and derived PK parameters of MAK683
Pre-and post-treatment expression of H3K27 trimethylation in blood
Phase II part:
Duration of overall response (DOR), Progression-free survival (PFS) and Best Overall Response (BOR)
Safety: Incidence and severity of AEs and SAEs, including changes in laboratory parameters, vital signs and ECGs
Tolerability: Dose interruptions, reductions and dose intensity.
Plasma concentrations and PK profiles of MAK683
Pre-and post-treatment expression level of H3K27 trimethylation in blood |
Parte di Fase I:
- Tasso di risposta complessiva (ORR), durata della risposta complessiva (DOR), sopravvivenza libera da progressione (PFS) e migliore risposta complessiva (BOR)
- Concentrazioni plasmatiche e parametri farmacocinetici derivati di MAK683
- Livello di espressione pre e post-trattamento della trimetilazione H3K27 nelle cellule mononucleari del sangue
Parte di Fase II:
- Durata della risposta complessiva (DOR), sopravvivenza libera da progressione (PFS) e migliore risposta complessiva (BOR)
Sicurezza d¿impiego: Incidenza e gravit¿ degli eventi avversi e degli eventi avversi seri, comprese le alterazioni dei parametri di laboratorio, dei segni vitali e degli elettrocardiogrammi (ECG)
Tollerabilit¿: Interruzioni della dose, riduzioni della dose e intensit¿ della dose
Concentrazioni plasmatiche e parametri farmacocinetici derivati di MAK683
Livello di espressione pre e post-trattamento della trimetilazione H3K27 nelle cellule mononucleari del sangue |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of study |
| A fine studio |
|
| 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 | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | No |
| 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 | 7 |
| 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 | 7 |
| 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 | Information not present in EudraCT |
| 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 |
| Canada |
| China |
| Hong Kong |
| Japan |
| Korea, Republic of |
| Singapore |
| United States |
| France |
| Germany |
| Italy |
| Netherlands |
| Spain |
|
| 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
|
| The study will end when the treatment period, 30-day safety follow-up and progression disease follow up (if applicable) have completed for all patients or if the study is terminated early. |
| - |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| 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 | 2 |
| 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 |
Print
