Primary: Part 1: Safety and tolerability. Determine the MTD and/or RP2D of MAK683.Part 2: Anti-tumor activity of MAK683.Secondary: Part 1: Anti-tumor activity. Pharmacodynamics (PD). Pharmacokinetics (PK).Part 2: Safety and tolerability. PK, PD.
ID
Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase 1
Safety: DLTs, Incidence and severity of AE's and serious AE's,
Tolerability: Dose interruptions, reductions and dose intensity
Phase 2 : Overall response rate (ORR).
Secondary outcome
Phase I part
Overall Response Rate (ORR), Duration of Overall Response (DOR),
Progression-FreeSsurvival PFS) and Best Overall Response (BOR).
PK parameters, pre- and posttreatment expression of H3K27 tri methylationin
PBsMC
Phase II part
DOR, PFS and BOR
Safety: DLTs, Incidence and severity of AE's and serious AE
Tolerability: Dose interruptions, reductions and dose intensity
PK parameters
Pre- and post treatment expression of H3K27 tri methylation in PBMC
Background summary
PRC2 is an important methyltransferase complex that modifies the epigenetic
status of target genes such as tumor suppressor genes, DNA repair genes and
cell cycle control genes. EZH2 in conjunction with EED-subunits of PRC2
functions as a histone methyltransferase for H3K27 and in turn repressing
target genes.
EZH2 overexpression has been shown to contribute to neoplastic transformation,
tumor aggressiveness and portends a poor prognosis in several tumor types
including lymphoma, Nasopharyngeal carcinoma, prostate cancer, ovarian cancers,
gastric tumors and multiple solid tumor malignancies.
MAK683 is a selective, potent and first-in -class EED inhibitor and has
demonstrated in vitro inhibitory activity and in vivo anti-tumor activity in
several preclinical tumor models, including DLBCL, nasopharyngeal carcinoma and
other solid tumors.
Study objective
Primary:
Part 1: Safety and tolerability. Determine the MTD and/or RP2D of MAK683.
Part 2: Anti-tumor activity of MAK683.
Secondary:
Part 1: Anti-tumor activity. Pharmacodynamics (PD). Pharmacokinetics (PK).
Part 2: Safety and tolerability. PK, PD.
Study design
Phase I/II, multi-center, open-label dose escalation and dose expansion study.
Prescreening (tumor tissue) for subjects with DLBCL and nasopharyngeal
carcinoma.
Food-effect study in 12 patients
Appr. 148 subjects (100 phase 2 part).Treatment until disease progression or
unacceptable toxicity.
Intervention
Treatment with MAK683.
Oral intake QD. other schedules may be explored.
Study burden and risks
Possible Adverse effects of MAK683 (based on animal studies)
- Side effects related to digestive system, blood cell count and function,
liver and skin were seen in animal studies. Most of the abnormalities seen in
animals got better after stopping treatment with MAK683.
- An increase in heart rate was observed in dog following single high dose.
- Based on these results of animal studies the most likely and most severe side
effects of MAK683 are expected to include effects such as vomiting, diarrhea
and bodyweight loss.
- In dogs and rats studies, side effects were also observed in the male
reproductive organ (testis) which were not reversed during the 4 week recovery
period after stopping treatment. The animals were not observed beyond this 4
week period. It is however, not known whether MAK683 has any effect on the
testis in humans.
Risks and inconveniences of the assessments as radiation, bleeding after
blooddraw and/or tumorbiopsy
Burden:
Cycles of 4 weeks. cycle 1: 6 visits,, cylce 2: 5 visits, subsequent cycles: 2
visit each cycle.
Physical examination: every visit.
Blood tests: 4 times (cycle 1,2), 2 times (cycle 3,4), once (cycle 5 onwards);
3-18 mL/occasion plus PK and biomarkers (160 ml in total).
Pregnancy test: every cycle.
ECG: .phase 1: 6x cycle 1 day 1 and 6x cycle 1 day 8, 4x cycle 2, thereafter 1x
each cycle and at end of treatment.
Echocardiogram or MUGA: 3 times.
Abdominal ultrasound (liver and biliary tract): 3 times.
Tumor measurements: baseline, cycle 3 and every 8 weeks thereafter. During
follow up for progression every 8-12 weeks.
Tumor biopsy once at baseline and at cycle 1 day 15 (optional for patients with
DLBCL).
Two optional skinbiopsies (prior to first dose of MAK683 and on-treatment Cycle
1)
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
- ECOG performance status 0 to 2
- Patients progressed after standard therapy or are intolerant of standard therapy or for whom no standard therapy exists
- Measurable disease according to RECIST v1.1 for patients with solid tumors or Cheson criteria for patients with DLBCL
- Patients must have a site of disease amenable for biopsy. On-Treatment biopsy (C1D15) is required for patients with solid tumors
- Histologically or cytologically confirmed diagnosis required for all indications
- Patients with DLBCL: documentation of EZH2 mutational status required in phase II
- Patients with NPC: documentation of presence of p16/CDKN2A gene required
- Patients with ovarian cancer must have a primary tumor wiith great than 50% clear cell histomorphology
- Patients with prostate cancer must have evidence of castration resistance: a confirmed rising PSA and a castrate-serum testosterone level (i.e. * 50 mg/dL);
- Patients with sarcoma: Enrollment is limited to epithelioid sarcoma, other types of sarcoma with SWI/SNF alterations may be considered with approval from Novartis.;Other protocol inclusion criteria may apply (section 5.2)
Exclusion criteria
- Other malignant disease than the one being treated in this study
- 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.
- B-cell lymphoma patients who have received prior allogeneic stem cell transplant
- Patient have received anti-cancer therapies within defined time frames prior to the first dose of study treatment (protocol section 5.3 bullet 10)
- CNS involvement which are neurologically unstable or requiring increasing doses of steroids to control.
- Insufficient bone marrow function at screening: Platelets * 50 x 109/L (50,000/mm3) - Hemoglobin (Hgb) * 90 g/L (9 g/dL) - Absolute neutrophil count (ANC) * 1.0 x 109/L (1000/mm3)
- Insufficient hepatic and renal function at screening: ALP, ALT, and AST > 3 x ULN (>5 x ULN if subject has liver metastases) - Total bilirubin *2 x ULN - Serum creatinine > 1.5 x ULN and/or creatinine clearance * 50 mL/min
- Unable to stop any prohibited medications, including strong CYP3A4 inhibitors or inducers, CYP3A4 or CYP2C8 substrates with a narrow therapeutic index, long acting proton pump inhibitors.;Other protocol-defined exclusion criteria may apply (protocol section 5.3)
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-001860-12-NL |
| ClinicalTrials.gov | NCT02900651 |
| CCMO | NL63879.041.17 |