The primary objectives for Part 1:-To determine the recommended Phase II dose of RO5424802 to be used in Part 2 of the study-To evaluate the safety and tolerability of 600mg and 900mg doses of RO5424802 administered twice daily to subjects with…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms benign (excl mesotheliomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part 1
1. Determination of a Phase II recommended dose
2. Incidence of DLTs by NCI CTCAE v4.03 grade and associated dose of
RO5424802 (600 and 900 mg twice a day [BID])
3. Plasma PK analysis for RO5424802
Part 2
4. Objective tumor response rate (ORR) (Partial response [PR] and
Complete response [CR]) as assessed by an independent radiological
review committee using RECIST v1.1
Secondary outcome
1. ORR (PR and CR) as assessed by IRC using RECIST v1.1 in subjects without
prior exposure of cytotoxic chemotherapy treatment(s)
2. ORR (PR and CR) as assessed by the investigator using RECIST v1.1
3. Disease control rate based on IIRR
4. Duration of Response based on IIRR
5. Progression Free Survival based on IIRR
6. CNS Objective Response Rate in subjects with measurable disease in the CNS
metastasis as assessed by IRC
7. Duration of CNS Response as assessed by IRC
8. CNS progression rate as assessed by IRC
9. Overall Survival
Background summary
Survival rates for lung cancer tend to be much lower than other common cancers
due to late diagnosis and limited effective therapy in advance stage.
Conventional chemotherapy has achieved some benefit but there remains a
significant clinical unmet need. Recent studies have shown that non-small cell
lung cancer (NSCLC) carries mutations in receptors for various key signal
transduction mediators, such as epidermal growth factor receptor (EGFR), MET,
anaplastic lymphoma kinase (ALK), KRAS, and phosphoinositide 3-kinase (Pi3K).
Mutations in EGFR and ALK are particularly important in driving tumorigenesis
via pathway addiction. These findings led to the successful development of
targeted therapies that inhibit these pathways.
Crizotinib is the only approved drug for the treatment of ALK-positive NSCLC in
the United States and Europe. Unfortunately, despite robust early efficacy,
NSCLC develops resistance to the targeted therapeutic agents after approx. 10
months.
Available non-clinical and clinical data demonstrate RO5424802 is active in
NSCLC even after progression on prior crizotinib therapy.
Study objective
The primary objectives for Part 1:
-To determine the recommended Phase II dose of RO5424802 to be used in Part 2
of the study
-To evaluate the safety and tolerability of 600mg and 900mg doses of RO5424802
administered twice daily to subjects with locally advanced or
metastatic NSCLC who have ALK rearrangement and in whom prior crizotinib
therapy has failed
-To characterize dose-limiting toxicities, if any, associated with RO5424802
after 21 days of treatment when administered twice daily at
600- and 900mg doses to subjects with locally advanced or metastatic NSCLC who
have ALK re-arrangement and in whom prior crizotinib
therapy has failed
-To characterize the pharmacokinetics of RO5424802
The primary efficacy objectives for Part 2:
•To evaluate efficacy of RO5424802 by objective response rate (ORR) as per
central independent radiological review committee (IRC) using
Response Evaluation Criteria in Soid Tumors (RECIST) criteria version 1.1 in
the overall population.
Additional secondary objectives for the overall population:
-To evaluate efficacy of RO5424802 by ORR as per central IRC using RECIST
criteria version 1.1 in subjects without prior exposure of cytotoxic
chemotherapy treatment(s)
-To evaluate efficacy of RO5424802 by ORR per investigator review of
radiographs using RECIST 1.1
-To evaluate disease control rate (DCR) of RO5424802 based on IRC and
investigator review of radiographs (IIRR)
-To assess duration of response (DOR) in subjects treated with RO5424802 based
on IIRR
-To evaluate the progression-free survival (PFS) in subjects treated with
RO5424802 based on IIRR
-To evaluate central nervous system (CNS) ORR in subjects with CNS metastases
who have measurable disease in the CNS at baseline, based
on IRC review of radiographs (IRR)
-To assess CNS DOR in subjects who have a CNS Objective Response based on IRR
-To assess CNS progression rates (CPR) at 3, 6, 9 and 12 months based on
cumulative incidence by IRR
-To assess overall survival (OS)
Study design
The study will be conducted in three parts. Patients will be treated
continuously until disease progression, death, or withdrawal for any other
reasons in all 3 parts of the study. Each treatment cycle will consist of 28
days.
Part 1 - Determination of a Phase II Recommended Dose - Dose Escalation Study
A dose-escalation phase will be included in study NP28673 to assess the safety,
tolerability, and PK of 600 mg BID and 900 mg BID dose regimens in Part 1.
A 3+3 design will be used for this portion of the study. NSCLC patients
enrolled in this portion of the study should have been previously treated and
experienced disease progression on crizotinib. Enrolment of more than 3
patients will be allowed even without DLTs based on tolerability and the PK
analysis. Up to 12 patients will be enrolled in the dose escalation portion.
All doses of RO5424802 will be administered within 30 minutes after a meal.
Doses of RO5424802 up to 900 mg BID have been established to be well tolerated
in Study AF-002JG with no DLTs reported at any dose levels and up to 900 mg
BID. To-date, patients have received RO5424802 administered using the 20 and 40
mg capsule strengths. Part 1 of this study will enroll patients to evaluate the
safety, tolerability, and PK of RO5424802 administered at 600 mg BID using the
150 mg capsule strength to facilitate use in Part 2 of this study. In the dose
escalation portion of study NP28673, the first 3 patients will start receiving
RO5424802 at a dose of 600 mg (4 * 150-mg capsules) BID. Patients will be
observed for DLT during a 21-day treatment/safety assessment period. Safety,
tolerability, and PK of RO5424802 will be evaluated in this 21-day treatment
period. If 1 DLT is observed in the 600-mg cohort, then this cohort will be
expanded to 6 patients. If necessary, additional patients may be added to
further characterize PK.
The 900 mg BID dose level may be conducted to further characterize the safety,
tolerability, and PK of RO5424802 administered using the 150 mg capsule
strenght. Three patients will start receiving RO5424802 at a dose of 900 mg (6
x 150-mg capsules) BID. Patients will be observed for DLT during a 21-day
treatment/safety assessment period. Safety, tolerability, and PK of RO5424802
will be evaluated in this 21-day period. If 1 DLT is observed in the 900-mg
cohort, then this cohort will be expanded to 6 patients.
If 2 or more DLTs are observed in either cohort, then the next lower dose
evaluated will be deemed the RP2D dose and used in Part 2 of the study. If the
600-mg dose is not tolerated, then a 450 mg dose will be considered as the RP2D
for Part 2 of the study. The tolerability of the 450 mg dose was established by
evaluation of that cohort in Study AF-002JG. The doses tested in this study
should not exceed the maximum tolerated dose (MTD) of Study AF-002JG. If a dose
is determined to be the MTD from Study AF-002JG, then this dose will be used as
the RP2D in this study. No further escalations will be considered in this study
and Part 1 of this study will repeat assessments for the RP2D in at least 6
patients before beginning Part 2.
If no DLT within the first 3 patients, or no more than one DLT within 6
patients, is observed during the evaluation of the 900 mg BID dose, then this
dose will be considered as the RP2D for the second portion of study NP28673.
The MTD cohort should include 6 patients before being established as the RP2D.
The DLTs will be assessed during a 21-day treatment/safety assessment period.
DLTs are defined as drug-related toxicities that meet any one of the following
criteria:
• Grade 4 thrombocytopenia
• Grade 3 thrombocytopenia with bleeding
• Grade 4 neutropenia continuing for >=7 consecutive days or neutropenic fever
• Non-hematological toxicity of Grade 3 or higher, excluding the following:
Transient electrolyte abnormalities and corrected in less than 2 days
Diarrhea, nausea, and vomiting that recover to Grade 2 or lower with
appropriate treatment
Grade 3 or higher AST or ALT when Grade 2 AST or ALT was present at baseline
(unless Grade 3 AST or ALT is present for 7 days or Grade 4 AST or ALT is
observed
• Adverse events that require suspension of treatment for a total of >=7 days
The RP2D will be determined based on the MTD, safety and PK of RO5424802.
Additional dose levels may be explored, with review of safety, tolerability,
and PK.
All patients will continue to be treated at the same dose until progression,
following the Schedule of Assessments in Part 2 (See Appendix 1).
Part 2 - Evaluation of Safety and Efficacy of RO5424802 in ALK-positive NSCLC
Patients with ALK Rearrangements.
Once the RP2D has been determined (see Part 1), Part 2 of the study will be
initiated. Part 2 is a Phase II open label, non-randomized, multicenter study
in patients with NSCLC with ALK rearrangement(s) who have experienced disease
progression on crizotinib. All patients will receive RO5424802 at the
recommended dose determined in Part 1 until their disease progresses.
A Simon two-stage study design will be used and a non-binding futility analysis
will be performed when at least 30 patients in Part 2 have a response at 8
weeks post-treatment available, by investigator assessment. During the period
waiting for a response amongst the first 30 patients, regardless of previous
chemotherapy treatment(s), the study will continue with ongoing enrollment. If
the futility analysis result shows that the response rate does not achieve 30%,
then the study may be terminated due to futility. Otherwise, enrollment will
stop when approximately 130 ALK-positive NSCLC patients in total are enrolled
into the study. A minimum of 85 patients who received at least one line of
platinum based chemotherapy and a maximum of up to 45 patients who are naïve to
any cytotoxic chemotherapy will be enrolled. If necessary, enrollment of
chemo-naïve patients will be stopped to ensure the minimum of 85 is reached for
the patients who received at least one line of platinum-based chemotherapy.
Part 3 - Post-progression treatment
Following progression of disease, patients whose tumor specimens do not show
EGFR mutation in the pre-treatment biopsy, or patients who did not consent to
the optional pre-treatment biopsy (i.e., EGFR mutation unknown) will be offered
continued treatment with RO5424802, should their treating physicians consider
that they are benefiting.
Patients who progressed on RO5424802, and whose tumor tissue shows EGFR
mutations (e.g., Exon19 deletion or L858R in Exon21) will be offered a
combination of RO5424802 at the RP2D and erlotinib at 100 mg QD.
Patients can also elect to be taken off study medication and seek other
treatment options outside of this study.
The midazolam sub-study was included into the main NP28673 protocol, this
drug-drug interaction sub-study will only run in a very limited number of
countries. The midazolam sub-study will not run in the Netherlands.
Intervention
RO5424802 will be orally administered daily within 30 minutes after meals in
the morning and evening.
Study burden and risks
There are no guaranteed benefits from this study, and taking part in this
study may or may not cause the patients health to improve. Information from
this study may help doctors learn more about RO5424802 and the treatment of
NSCLC. This information may benefit other patients with NSCLC or a similar
condition in the future.
Grenzacherstrasse 124
Basel 4070
CH
Grenzacherstrasse 124
Basel 4070
CH
Listed location countries
Age
Inclusion criteria
-Patients with locally advanced (AJCC stage IIIB) not amenable to curative therapy or metastatic (AJCC stage IV) NSCLC
-Male or female >=18 years old
-Life expectancy, in the opinion of the investigator, of at least 12 weeks
-Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
-Histologically confirmed NSCLC
-Documented ALK rearrangement based on a Food and Drug Administration (FDA) approved test
-Prior treatment with crizotinib and progression based on RECIST criteria version 1.1. Subjects need to have a minimum 1-week wash-out period between the last dose of crizotinib and the first dose of study treatment (for patients enrolled in the midazolam substudy). Subjects can either be chemotherapynaïve or have received at least one line of platinum-based chemotherapy for locally advanced or metastatic disease
-Adequate hematologic function
-Adequate hepatic function
-Adequate renal function
-Recovery from effects of any major surgery or significant traumatic injury at least 28 days before the first dose of study treatment
-Subjects with brain or leptomeningeal metastases are allowed on study if they have previously been treated with Whole brain radiotherapy (WBRT) or gamma-knife radiosurgery. Subjects must have completed treatment, be clinically stable and have discontinued the use of corticosteroids for this indication for>=2 weeks. If not previously treated with WBRT or gamma-knife radiosurgery, subjects must have been asymptomatic without neurological signs and clinically stable for >=2 weeks without steroid treatment prior to first dose
-Measurable disease (by RECIST criteria version 1.1) prior to the first dose of study treatment
-Negative pregnancy test within 10 days of first dose for women of child bearing potential
-For women of childbearing potential: agreement to remain abstinent or use contraceptive methods that result in a failure rate of < 1% per year during the treatment period and for at least 3 months after the last dose of study drug
-For men: agreement to use a barrier method of contraception during the treatment period and for at least 3 months after the last dose.;The midazolam sub-study was included into the main NP28673 protocol, this drug-drug interaction sub-study will only run in a very limited number of countries. The midazolam sub-study will not run in the Netherlands. Therefore new criteria not applicable.
Exclusion criteria
1.Receipt of any other ALK inhibitors in addition to crizotinib
2.Receipt of any prior cytotoxic chemotherapy for ALK-positive NSCLC within 4 weeks prior to the first dose of study treatment. Patients who received crizotinib or other tyrosine kinase inhibitors need to have a minimum 1-week wash-out period before the first dose of study treatment
3.A previous malignancy within the past 3 years (other than curatively treated basal cell carcinoma of the skin, early gastrointestinal cancer by endoscopic resection, in situ carcinoma of the cervix or any cured cancer that is considered to have no impact on PFS and OS for the current NSCLC)
4.Active or uncontrolled infectious diseases requiring treatment
5.National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) (version 4.03) Grade 3 or higher toxicities due to prior therapy that has not shown improvement and are considered to interfere with current study medication.
6.History of organ transplant
7.Co-administration of anti-cancer therapies other than those administered in this study.
8. Baseline QTc >470 ms, or baseline symptomatic bradycardia <45 beats per minute
9. Known HIV positivity or AIDS-related illness
10. Any significant concomitant disease
11. Administration of strong/ potent CYP3A inhibitors or inducers within 14 days prior to first administration of study drug
12. History of hypersensitivity to any of the additives in the RO5424802 formulation
13. Any clinically significant concomitant disease
14. Any psychological, familial, sociological or geographical condition;The midazolam sub-study was included into the main NP28673 protocol, this drug-drug interaction sub-study will only run in a very limited number of countries. The midazolam sub-study will not run in the Netherlands. Therefore new criteria not applicable.
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 | EUCTR2012-004455-36-NL |
| CCMO | NL43288.031.13 |