Primary: To characterize safety and tolerability of LTT462 and identify a recommended dose and regimen for future studies in adult patients with advanced solid tumors harboring MAPK pathway alterations. Secondary: Preliminary anti-tumor activity,…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety:
Incidence and severity of adverse events (AEs) and serious AEs (SAEs).
Incidence and nature of DLTs (dose escalation only)
Tolerability:
Dose interruptions, reductions, and dose intensity
Secondary outcome
Overall response rate, disease control rate, duration of response, progression
free survival, PK, changes from baseline of the PD marker DUSP6 in tumor tissue
and in blood.
Background summary
MAPK pathway is frequently activated in human cancers with RAS genes (KRAS,
NRAS and HRAS) being the most frequently mutated oncogenes in all cancers
(>30%) with KRAS mutations being the most prevalent in 20% of all cancers.
However, no effective therapies exist for KRAS mutant cancers.
Inhibitors against BRAF or MEK suppress MAPK signaling and have demonstrated
efficacy in BRAF mutant tumors, but these effects are almost always short-lived
due to multiple acquired resistance mechanisms which commonly reactivate ERK1/2
signaling. In this setting, inhibition of ERK1/2, which are the most distal
kinases in the MAPK signaling cascade, effectively inhibits MAPK signaling and
demonstrates anti-tumor effects in preclinical studies. LTT462 has shown
efficacy in a wide range of MAPK pathway-driven human cancer cell lines and in
vivo tumor xenografts including models harboring activating lesions in the
KRAS, NRAS, MEK and BRAF oncogenes. Therefore it is expected that the ERK1/2
inhibitor LTT462 will result in anti-tumor activity in adult patients with
advanced solid tumors harboring documented MAPK pathway alterations.
The purpose of this first-in-human trial is to characterize safety and
tolerability of the ERK1/2 inhibitor LTT462 and identify a recommended dose and
regimen for future studies in adult patients with advanced solid tumors
harboring mitogen activated protein kinase (MAPK) pathway alterations.
Study objective
Primary:
To characterize safety and tolerability of LTT462 and identify a recommended
dose and regimen for future studies in adult patients with advanced solid
tumors harboring MAPK pathway alterations.
Secondary:
Preliminary anti-tumor activity, pharmacokinetic profile, pharmacodynamic
profile
Study design
Multicenter phase I open-label dose finding study with a dose escalation part
and a dose expansion part. Treatment with LTT462 until disease progression or
unacceptable toxicity.
Food effect sub-study in a subset of subjects in expansion phase. Follow-up for
survival in expansion part/
21 subjects in escalation part and 50 in expansion part. If needed enrolment
may be increased up to 250 subjects
Intervention
LTT462
Daily oral dosing. Fixed dose
Study burden and risks
- Risk: Adverse effects of LTT462 (first in humans study).
- Burden: Cycles of 4 weeks. Cycle 1: 7-8 visits, cycle 2: 4 visits, cycle 3-6:
2 visits and thereafter 1 visit per cycle. Duration mostly 1-4 hours. Two
visits (cycle 10 will take 7-9, resp. 11-13hrs.
- Physical examination: once per cycle.
- Blood draws/tests (mostly 15-30 ml/occasion): nearly every visit. Additional
blooddraws for Pk and biomarkers.
- ECG: multiple ECG's at screening and pre- / post intake of LTT462 for the
first 6 cycle and at End of Treatment.
- MUGA scan (or echocardiography): 3 times.
- CT-/MRI scan: every 8 weeks.
- Eye examinations (incl. OCT and fundoscopy with dilatation of the pupil): 5
times.
- maximal 3 tumor biopsies.
- Optional storage and use of tumor tissue and blood for future research.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
1. >=12 years of age (in Netherlands: >=18 years of age)
2. Must have progressed following standard therapy, or, in the opinion of the Investigator, no effective, tolerated or appropriate standard therapy.
3. ECOG performance status 0, 1.
4. Presence of at least one measurable lesion (RECIST v1.1).
5. Archival tumor tissue or fresh tumor tissue at screening.
6. Patients must be willing to undergo study required biopsies.;Dose escalation part:
• Advanced solid tumors harboring at least one of the MAPK pathway alterations.;Dose expansion part:
• Group 1: confirmed KRAS and/or BRAF-mutated NSCLC.
• Group 2: confirmed KRAS and/or BRAF-mutated ovarian cancer.
• Group 3: BRAFV600 mutated melanoma. Initial response to, or stable disease for at least 6 months on a BRAFi and/or MEKi but then relapse. BRAFi and/or MEKi as the last line of treatment prior to entry into the study, or only one immunotherapy agent (e.g. anti-CTLA-4, anti PD-1, anti-PD-L1) following BRAFi and/or MEKi failure.
• Group 4: other advanced solid tumors harboring documented MAPK pathway alteration(s) other than those defined in Group 1, 2 and 3. ;Other criteria may apply. See protocol page 39-40 for more details.
Exclusion criteria
1. Prior treatment with ERK inhibitors.
2. History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO.
3. Other severe, acute or chronic medical condition that prevent the patient*s participation in the clinical study due to safety concerns
4. Treatment with strong inhibitors and/or inducers of CYP3A and CYP2C8; substrates of CYP3A with a narrow therapeutic index; and sensitive substrates of CYP3A, which cannot be discontinued 7 days prior to the start study treatment.
5. Proton pump inhibitors which cannot be discontinued 3 days prior to the start of study treatment.
6. Clinically significant cardiac disease.
7. Insufficient bone marrow function at screening: Absolute Neutrophil Count (ANC) < 1.5 x 109/L, Hemoglobin (Hgb) < 9.0 g/dL, Platelets < 75 x 109/L
8. Insufficient hepatic and renal function at screening: total bilirubin > 1.5 x upper limit of normal (ULN), AST or ALT > 3 x ULN or > 5.0 x ULN if liver metastases are present, creatinine > 1.5 x ULN
9. Pregnancy, lactation, insufficient contraception for females of childbearing potential.;Other criteria may apply. See protocol page 40-43 for more details.
Design
Recruitment
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 | EUCTR2015-003614-24-NL |
| ClinicalTrials.gov | NCT02711345 |
| CCMO | NL57739.031.16 |