Given the limited effectiveness of available EGFR TKIs in patients with NSCLC with EGFR exon 20 insertion mutations, this subset patient population is routinely treated with chemotherapy, similar to patients with no driver mutations (ie, WT EGFR).…
ID
Source
Brief title
Condition
- Respiratory and mediastinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- To compare the efficacy of TAK-788 as first-line treatment with that of
platinum-based chemotherapy in patients with locally advanced or metastatic
NSCLC whose tumors harbor EGFR exon 20 insertion mutations, as evidenced by
progression-free survival (PFS) as assessed by blinded independent review
committee (IRC) per Response Evaluation Criteria in Solid Tumors (RECIST)
version 1.1.
- To assess the safety and tolerability of TAK-788 in comparison with
platinum-based chemotherapy.
Secondary outcome
• To compare secondary measures of clinical efficacy of TAK-788 to that of
platinum-based chemotherapy, as evidenced by confirmed objective response rate
(ORR), time to response, duration of response, disease control rate (DCR) per
IRC and the investigator, and overall survival (OS) per the investigator.
• To compare patient-reported symptoms (particular core symptoms of lung
cancer), functioning, and health related quality of life (HRQoL) with the
European Organisation for Research and Treatment of Cancer (EORTC) Quality of
Life Questionnaire (QLQ)-C30 and the EORTC lung cancer module, QLQ LC13, in
patients treated with TAK 788 compared with those treated with platinum-based
chemotherapy.
• To collect pharmacokinetics (PK) of TAK 788 and its active metabolites,
AP32960 and AP32914, to contribute to population PK and exposure-response
analyses (TAK-788 group only).
Background summary
Of the 2 main histologic types of lung cancer (small cell lung cancer and non-
small cell lung cancer [NSCLC]), NSCLC represents over 85% of all lung cancers.
The majority of patients with NSCLC present with either locally advanced or
metastatic disease, with 70% to 80% of patients presenting with potentially
inoperable, later-stage disease, thereby contributing to a 5-year overall
survival (OS) rate of approximately 15% to 17%. NSCLC with EGFR (Epidermal
Growth Factor Receptor) exon 20 insertion mutations is a life-threatening
disease involving rare mutations for which there is currently no approved or
adequate therapy available, and constitutes a distinct, well-defined patient
population with urgent unmet medical needs, regardless of prior treatment
history. Several different EGFR TKIs (eg, erlotinib, gefitinib, afatinib,
osimertinib) have been tested nonclinically and clinically with limited
clinical benefit observed in patients with EGFR exon 20 insertion mutations.
Given the limited treatment options, new target therapy more specifically
inhibiting EGFR exon 20 insertion mutations while sparing WT EGFR inhibition
will bring tremendous hope for this underserved patient population.
TAK-788 is an irreversible TKI that forms a covalent bond with cysteine 797 in
EGFR, which results in increased selectivity/potency and sustained inhibition
of EGFR signaling. TAK-788 was designed to address the limitations of current
EGFR TKIs. It has superior potency against EGFR exon 20 insertion mutations,
which has been improved using iterative, structure-guided design. It has
enhanced potency for mutant EGFR over WT EGFR, which is intended to reduce
dose-limiting, class-related toxicities (eg, rash and diarrhea). TAK-788 is
being evaluated in 1 ongoing global phase 1/2 clinical efficacy and safety
study (Study AP32788-15-101) in patients with NSCLC and multiple ongoing
clinical pharmacology studies.
Study objective
Given the limited effectiveness of available EGFR TKIs in patients with NSCLC
with EGFR exon 20 insertion mutations, this subset patient population is
routinely treated with chemotherapy, similar to patients with no driver
mutations (ie, WT EGFR). However, the benefits of the standard chemotherapy are
limited with typical safety concerns related to chemotherapy treatment. TAK-788
has shown promising activity in refractory NSCLC with EGFR exon 20 insertion
mutations at 160 mg QD orally in the analysis of Parts 1 and 2 (dose escalation
and expansion phases) of Study AP32788-15-101 with a tolerable safety profile.
The effectiveness and safety of TAK-788 as a first-line treatment in patients
with NSCLC with EGFR exon 20 insertion mutations will be examined in this
randomized and controlled study, in which the standard-of-care
(platinum-doublet chemotherapy) will be used as the active comparator.
Study design
This study is an open-label, multicenter, phase 3, randomized,
active-comparator study of TAK-788 in adult patients with NSCLC with EGFR exon
20 insertion mutations. The patient population will consist of adults diagnosed
with locally advanced or metastatic NSCLC whose tumors harbor EGFR exon 20
insertion mutations and who have not previously received systemic treatment for
locally advanced or metastatic disease. It is expected that approximately 318
patients will be randomized in this study. Determination of EGFR mutation
status for enrollment will be on the basis of a local test; confirmation of
EGFR mutation status in the tumor specimen will be performed retrospectively on
the basis of a central laboratory test analytically validated for the detection
of EGFR exon 20 insertion mutations and will not be required for enrollment.
Patients who are not centrally confirmed to have EGFR exon 20 insertion
mutations may continue to receive study drug if they are receiving clinical
benefit at the discretion of the investigator and with the sponsor*s approval;
these patients will continue in the study and continue study assessments per
the schedule of events. Once a patient has met all eligibility criteria, the
patient will be randomized in a 1:1 fashion to either TAK-788 orally (N = 159)
or platinum-based chemotherapy intravenously (IV) (investigator*s choice of
either pemetrexed/cisplatin or pemetrexed/carboplatin) (N = 159). Patients will
be stratified by the presence of CNS metastases at baseline (yes vs no) and
race (Asian vs non-Asian). Each treatment cycle is defined as 3 weeks (21
days). For the TAK-788 group (Arm A), TAK-788 will be administered at 160 mg
orally QD. Patients will continue to be treated with TAK-788 until they
experience PD as assessed by the IRC, intolerable toxicity, or another
discontinuation criterion. Treatment with TAK-788 may be continued after PD, at
the discretion of the investigator and with the sponsor*s approval, if there is
still evidence of clinical benefit. For the chemotherapy group (Arm B),
platinum-based chemotherapy will be administered IV on Day 1 of each cycle,
followed by a rest period of 20 days. Pemetrexed/cisplatin or
pemetrexed/carboplatin will be repeated every 3 weeks for 4 cycles followed by
maintenance treatment with pemetrexed on Day 1 of each 21-day cycle thereafter.
Treatment will continue until PD, as assessed by the IRC, intolerable toxicity,
or another discontinuation criterion. Treatment with chemotherapy may be
continued after PD, at the discretion of the investigator and with the
sponsor*s approval, if there is still evidence of clinical benefit. At the
discretion of the investigator with the sponsor*s approval, patients in the
chemotherapy group may cross over to treatment with TAK-788 after IRC-assessed
PD is documented and crossover eligibility criteria (Section 8.1.2.1) are met.
All patients who cross over to TAK-788 must have a washout period of at least 7
days between treatments and will start TAK-788 within 28 days after
IRC-assessed PD.
Patients who permanently discontinue study drug without IRC-assessed PD will
continue efficacy assessments in the posttreatment follow-up phase. The
posttreatment follow-up phase will continue until IRC-assessed PD, start of new
anticancer therapy, withdrawal of consent for further disease assessments, loss
to follow-up, death, pregnancy, or study termination by the sponsor. After the
posttreatment follow-up phase, patients may either cross over to TAK-788 (if
originally randomized to the chemotherapy group, IRC-assessed PD is documented,
and crossover eligibility criteria are met) or enter the survival follow-up
phase. Patients who discontinue study drug will enter either the posttreatment
follow-up phase (if patient discontinued without IRC-assessed PD) to continue
efficacy assessments or the survival follow-up phase to be followed for
survival; subsequent anticancer therapy; subsequent disease assessment outcome
until the first disease progression on a subsequent anticancer therapy; and
patient-reported health status (EQ-5D-5L) until death, loss to follow-up,
withdrawal of consent for survival follow-up, or the end of the study.
Radiological evaluations (computed tomography [CT] scan or magnetic resonance
imaging [MRI] with contrast, unless contrast media is contraindicated) will be
employed to assess the status of the patient*s underlying disease. Laboratory
values, vital signs, electrocardiograms (ECGs), and AEs will be obtained to
evaluate the safety and tolerability of study drug. AEs will be evaluated
according to National Cancer Institute Common Terminology Criteria for Adverse
Events (NCI CTCAE), version 5.0, effective 27 November 2017 [34]. Blood samples
for PK of TAK-788 and its active metabolites, including, but not limited to,
AP32960 and AP32914, will be collected at prespecified time points for patients
in the TAK-788 group as described in the schedule of events (Appendix A). Tumor
tissue harvested either from the primary or a metastatic site and blood samples
will be obtained for central confirmation of EGFR mutation status and/or for
molecular profiling and exploratory biomarker studies as described in the
schedule of events (Appendix A). PROs will be collected by administering paper
questionnaires or questionnaires via an interactive voice response system or
other electronic method (Section 9.4.8) at prespecified time points according
to the schedule of events (Appendix A).
Intervention
TAK-788 group (Arm A): TAK-788 160 mg QD with or without a low-fat meal
Chemotherapy group (Arm B): Investigator*s choice of either:
• Pemetrexed/cisplatin: pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2), on
Day 1 of a 21-day cycle.
• Pemetrexed/carboplatin: pemetrexed (500 mg/m2) plus carboplatin, at a dose
calculated to produce an area under the curve (AUC) of 5 mg·min/mL, on Day 1 of
a 21-day cycle. The same calculated AUC should be used for all carboplatin
doses.
Pemetrexed/cisplatin or pemetrexed/carboplatin will be repeated every 3 weeks
for 4 cycles then followed by maintenance treatment with pemetrexed (500
mg/m2), on Day 1 of a 21-day cycle thereafter.
Study burden and risks
Clinical investigation of the potential benefit of TAK-788 is ongoing through a
comprehensive and global development plan that involves Study AP32788-15-101
(see Section 4.1.3.2). The current investigator*s brochure describes the known
safety profile of TAK-788. The known safety profile indicates that the types of
adverse events (AEs) reported with TAK-788 are generally manageable and
reversible. While some of these potential toxicities may be serious, they can
be managed by clinical monitoring and standard medical intervention or dose
modifications. Overall, the benefit-risk assessment for TAK-788 based on the
available experience is expected to be favorable.
Landsowne street 40
Cambridge, MA 02139
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Landsowne street 40
Cambridge, MA 02139
US
Listed location countries
Age
Inclusion criteria
• Male or female adult patients (aged 18 years or older, or as defined per
local regulations).
• Histologically or cytologically confirmed nonsquamous cell locally advanced
not suitable for definitive therapy, recurrent, or metastatic (Stage IV) NSCLC.
• A documented EGFR in-frame exon 20 insertion mutation sometimes referred to
as duplication (including A763_Y764insFQEA, V769_D770insASV [ASV duplication],
D770_N771insNPG, D770_N771insSVD [SVD duplication], H773_V774insNPH [NPH
duplication], or any other in-frame exon 20 insertion mutation) assessed by a
Clinical Laboratory Improvements Amendment-certified (United States [US] sites)
or an accredited (outside of the US) local laboratory. The local molecular
testing reports may be required by the sponsor to confirm the exon 20 insertion
mutation status. The EGFR exon 20 insertion mutation can be either alone or in
combination with other EGFR or HER2 mutations except EGFR mutations for which
there are approved EGFR tyrosine kinase inhibitors (ie, exon 19 del, L858R,
T790M, L861Q, G719X, or S768I, where X is any other amino acid).
• Adequate tumor tissue available, either from primary or metastatic sites, for
central laboratory confirmation of EGFR in-frame exon 20 insertion mutation.
Note: confirmation of central test positivity is not required before
randomization.
• At least 1 measurable lesion per RECIST version 1.1. Previously irradiated
lesions may not be used for target lesions, unless there is unambiguous
radiological progression after radiotherapy.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Adequate organ and hematologic function, as determined by the following:
-- Blood transfusions are permitted with a recommended >=14-day washout
period before blood samples are obtained for Cycle 1 Day 1 laboratory
evaluations. This washout period may be shortened if deemed medically necessary
by the principal investigator (but it must not
be <7 days).
- Alanine aminotransferase/aspartate aminotransferase <=2.5 times the upper
limit of the normal range (ULN; <=5 times the ULN is acceptable if liver
metastases are present).
- Total serum bilirubin <=1.5 times the ULN (<=3.0 times the ULN for patients
with Gilbert syndrome or if liver metastases are present).
- Estimated creatinine clearance >=45 mL/min (calculated by using the
Cockcroft-Gault equation).
- Serum albumin >=2 g/dL.
- Serum lipase <=1.5 times the ULN.
- Serum amylase <=1.5 times the ULN unless the increased serum amylase is due to
salivary isoenzymes.
- Absolute neutrophil count >=1500/µL.
- Platelets >=100,000/µL.
- Hemoglobin >=9 g/dL.
- Serum electrolytes within normal ranges (ie, calcium, magnesium,
potassium, and sodium) based on local laboratory testing.
Exclusion criteria
• Received prior systemic treatment for locally advanced or metastatic disease
(with the exception below):
Neoadjuvant or adjuvant chemotherapy/immune therapy for Stage I to III or
combined modality chemotherapy/radiation for locally advanced disease is
allowed if completed >6 months before the development of metastatic disease.
• Received radiotherapy <=14 days before randomization or has not recovered from
radiotherapy-related toxicities. Palliative radiation administered outside the
chest and brain, stereotactic radiosurgery, and stereotactic body radiotherapy
are allowed up to 7 days before randomization.
• Received a moderate or strong cytochrome P450 (CYP)3A inhibitor or moderate
or strong CYP3A inducer within 10 days before randomization.
• Had major surgery within 28 days before randomization. Minor surgical
procedures such as catheter placement or minimally invasive biopsies are
allowed.
• Have been diagnosed with another primary malignancy other than NSCLC, except
for adequately treated nonmelanoma skin cancer or cervical cancer in situ;
definitively treated nonmetastatic prostate cancer; or patients with another
primary malignancy who are definitively relapse-free with at least 3 years
elapsed since the diagnosis of the other primary malignancy.
• Have known active brain metastases (have either previously untreated
intracranial central nervous system [CNS] metastases or previously treated
intracranial CNS metastases with radiologically documented new or progressing
CNS lesions). Brain metastases are allowed if they have been treated with
surgery and/or radiation and have been stable without requiring corticosteroids
to control symptoms within 7 days before randomization and have no evidence of
new or enlarging brain metastases.
• Have current spinal cord compression (symptomatic or asymptomatic and
detected by radiographic imaging) or leptomeningeal disease (symptomatic or
asymptomatic).
• Currently being treated with medications known to be associated with the
development of torsades de pointes.
• Currently have or have had a history of interstitial lung disease, radiation
pneumonitis that required steroid treatment, or drug-related pneumonitis.
• Have an ongoing or active infection including, but not limited to, the
requirement for intravenous antibiotics, or a known history of HIV. Testing for
HIV is not required in the absence of history.
Note: Hepatitis B surface antigen-positive patients are allowed to enroll if
hepatitis B virus DNA is below 1000 copies/mL in the plasma. Patients who are
positive for anti-hepatitis C virus antibody can be enrolled but must not have
detectable hepatitis C virus RNA in the plasma.
• Received a live vaccine within 4 weeks before randomization per SmPCs for
pemetrexed, cisplatin,and carboplatin.
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 | EUCTR2019-001845-42-NL |
| CCMO | NL72252.028.19 |
| Other | WHO UTN: U1111-1232-6059 |