Primary: To characterize the safety and tolerability of LXH254 single agent and to identify recommended doses for future studies in adult patients with advanced solid tumors harboring MAPK pathway alterations.To characterize the safety and…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms benign
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Adverse events, DLTs.
Secondary outcome
Overall response rate, disease control rate, progression free survival,
duration of response, overall survival. PK parameters of LXH254 and PDR001.
DUSP6 (as PD marker) for LXH254, Emergence of anti-PDR001 antibodies: Presence
and/or concentration of anti-PDR001 antibodies. BA of a new LXH254 tablet
formulation compared to the current LXH254 formulation
Background summary
Dysregulation of the MAPK pathway is a common event in many malignancies. RAS
genes are amongst the most frequently mutated oncogenes (9-30%) in all cancers
with KRAS mutations being the most prevalent (86%) of all RAS-driven cancers.
BRAF inhibitors, which are efficacious in melanomas with the BRAF V600E
mutation, are found to be ineffective in RAS-mutant cancers. MEK inhibition has
not demonstrated robust clinical efficacy in patients with tumors harboring RAS
mutations. Thus, (K)RAS-mutant tumors remain a high unmet medical need for
which no effective treatment exists.
CRAF has been demonstrated to be the critical mediator of mutant KRAS-driven
development in many cancers including NSCLC and plays an essential role in
mediating paradoxical activation following BRAF inhibition.
LXH254 is a pan-RAF inhibitor. Taking into account published data on the
importance of CRAF in MAPK pathway regulation and based on promising
preclinical anti-tumor activity in in vitro and in vivo models, we have a
strong rationale to evaluate the safety, tolerability and the preliminary
anti-tumor activity of LXH254 in adult patients with advanced solid tumors
harboring documented MAPK pathway alterations, including RAS and/or BRAF
mutated NSCLC, ovarian cancer and BRAF mutated melanoma resistant to BRAF
and/or MEK inhibition.
Study objective
Primary:
To characterize the safety and tolerability of LXH254 single agent and to
identify recommended doses for future studies in adult patients with advanced
solid tumors harboring MAPK pathway alterations.
To characterize the safety and tolerability of LXH254 in combination with
PDR001 and identify a recommended dose and regimen for future studies in adult
patients with advanced NSCLC harboring KRAS mutations.
Secondary:
To evaluate the preliminary anti-tumor activity of LXH254 single agent and
LXH254 in combination with PDR001.
To evaluate the pharmacokinetic (PK) profile of LXH254 single agent and LXH254
in combination with PDR001.
To assess the pharmacodynamic (PD) effect of LXH254 single agent and LXH254 in
combination with PDR001.
To assess emergence of anti-PDR001 antobodies following one or more
intravenous (i.v.) infusions of PDR001.
Study design
Multicenter phase I open-label dose escalation and dose expansion study of
LXH254.
The dose escalation part will be performed in adult patients with advanced
solid tumors harboring documented MAPK pathway alterations. Primarily a once
daily regimen will be tested. If needed a twice daily regimen will be
investigated as well. Once the MTD/RP2D of LXH254 is achieved, the dose
expansion part will commence with selected indications (melanoma, NSCLC and
ovarian cancer). NSCLC patients may be treated with LXH254 in combination with
PDR001. Rare MAPK pathway alterations are also planned to be investigated in
the dose expansion phase.
For 12 patients the bioavailabiltiy of the LXH254 100mg and LXH254 200mg will
be compared.
The study treatment will be administered as oral tablets in cycles of 28 days.
Tablets will be taken in the fasting state. However in the dose expansion phase
the effect of a high fat high calorie meal will be assessed in the first
patients (n=12 evaluable patients) prior to the start of the treatment phase.
In case a food effect is observed, the effects of a low fat meal will also be
investigated.
Treatment until disease progression or unacceptable side effects.
Follow-up for survival in the expansion cohort.
Dose escalation approx. 21 subjects.
Dose expansion approx. 50 (max. 171) subjects.
Intervention
Treatment with LXH254 or LXH254+PDR001
Study burden and risks
-Risk:
Adverse effects of LXH254. Especialliy occurrences of several cases of
polyneuropathies (PNP) and similar
events occurring in a subset of patients after stopping or interrupting
treatment with LXH254.
Adverse effects of PDR001: Risk of Stevens-Johnson Syndrome (SJS)which mandates
stopping with PDR001
- First-in-human study with LXH254.
-Burden: Cycles of 4 weeks. Cycle 1 7 visits, cycle 2 4 visits, cycle 3-6 2
visits, from cycle 7 onwards 1 visit per cycle. Duration mostly 1-4 hours. Two
visits during cycle 1 with a duration of 7-9 hours and 11-13 hours,
respectively.
-Physical examination: once per cycle.
-Blood tests for safety (approx. 10-40 ml/occasion): nearly every visit.
Additional blood draws for PK, biomarkers.
-ECG: 4 times during cycle 1 (2 times multiple ECGs), 2 times during cycle 2
and once during cycles 3-6.
-Echocardiogram (or MUGA scan): 3 times in total.
-Ophthalmological examination: cycle 2, 3, 4 and final visit.
-2-3 tumor biopsies.
-CT-/MRI-scan: every 8 weeks.
-Optional storage and use of the remaining blood and tissue for future research.
- baseline neurological exam
Haaksbergweg 16
Amsterdam 1101 BX
NL
Haaksbergweg 16
Amsterdam 1101 BX
NL
Listed location countries
Age
Inclusion criteria
** 18 years old.
*Progressed following standard therapy, or, in the opinion of the Investigator,
no effective standard therapy exists, is tolerated or appropriate.
*Dose escalation part: Advanced solid tumors, harboring at least one MAPK
pathway alteration (see protocol Table 5-1) when enrolled in cohorts testing
LXH254 single agent or NSCLC patients and NRAS mutant melanoma patients with
specific mutations in the MAPK pathways for cohorts testing LXH254 in
combination with PDR001.
*Dose expansion part: other advanced solid tumors harboring documented MAPK
pathway alteration (protocol Table 5-1). These include but are not limited to:
-Confirmed KRAS and/or BRAF-mutated NSCLC.
-Confirmed KRAS and/or BRAF-mutated ovarian cancer.
-BRAF V600-mutated melanoma patients who are refractory to or relapsed on
prior BRAFi/MEKi combination therapy, NRAS-mutated melanoma
LXH254 in combination with PDR001: NSCLC patients with specific mutations in
the MAPK pathway and patients with NRAS mutated melanoma
-NRAS- mutated solid tumors,
*ECOG performance status 0-1
Exclusion criteria
*Prior treatment with a BRAF, MEK and/or pan-RAF inhibitor in patients with
confirmed KRAS and/or BRAF-mutated NSCLC and ovarian cancer in dose expansion
part.
*Prior treatment with any of the following (see protocol page 37 for details
incl. time frames): radiation, chemotherapy, cytotoxic agents with major
delayed toxicities, major surgery, immunotherapy.
*History or current evidence of retinal vein occlusion (RVO) or current risk
factors for RVO.
*Gilbert*s syndrome or other heritable diseases of bile processing.
*Clinically significant cardiac disease, see protocol page 38 for details.
*Out of range laboratory values. See protocol page 38-39 for details.
*Sexually active males unless they use a condom during intercourse.
*Pregnancy, lactation, insufficient contraception for females of childbearing
potential.
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 | EUCTR2015-003421-33-NL |
| ClinicalTrials.gov | NCT02607813 |
| CCMO | NL55506.078.15 |