This phase 1/2 study will evaluate the safety, pharmacokinetics, and anti-tumor activity of
oral EGFR/HER2 Inhibitor TAK-788 in participants with NSCLC and anti-tumor activity of
TAK-788 in participants with solid tumors other than NSCLC with EGFR or HER2 mutations. The
trial will be conducted in three parts: a dose escalation (Part 1), including Part 1A (dose
escalation combination component of TAK-788 in combination with Pemetrexed/Carboplatin) and
Part 1B (TAK-788 monotherapy and TAK-788 in combination with pemetrexed/carboplatin with
primary antidiarrhea prevention with loperamide.) and expansion phase (Part 2), followed by
an extension phase (Part 3).
The objectives of the dose escalation phase (Part 1),dose escalation combination phase (Part
1A, only for selected sites in the United States) and Antidiarrhea Prophylaxis Cohorts ( part
1B, only for selected sites in the United States) are to determine the safety profile of
orally administered TAK-788 and TAK-788 in combination with Pemetrexed/Carboplatin, including
the MTD, DLTs, RP2D,pharmacokinetic profile and with loperamide as primary antidiarrhea
prevention incidence and severity of TAK-788-associated diarrhea and anti-tumor activity of
TAK-788 (Part 1B) . The primary goal of the expansion component of the trial is to evaluate
the anti-tumor activity of TAK-788 in seven histologically and molecularly defined cohorts at
the RP2D (determined based on dose escalation phase of the trial).
The seven expansion cohorts will be:
1. NSCLC participants with EGFR exon 20 activating insertions, who have either not received
or not shown an objective response to an EGFR TKI, and who have no active, measurable
CNS metastases;
2. NSCLC participants with HER2 exon 20 activating insertions or point mutations and no
active, measurable CNS metastases;
3. NSCLC participants with EGFR exon 20 activating insertions or HER2 exon 20 activating
insertions or point mutations and active, measurable CNS metastases;
4. NSCLC participants with other targets against which TAK-788 is active (examples include
EGFR exon 19 deletions or exon 21 substitutions [with or without T790M mutations] and
other uncommon EGFR activating mutations), without active CNS metastases;
5. NSCLC participants with EGFR exon 20 activating insertions, who have previously shown an
objective response to an EGFR TKI and subsequently progressed, without active CNS
metastases;
6. NSCLC participants with EGFR exon 20 activating insertions, who have not received prior
systemic anticancer treatment for locally advanced or metastatic disease, without active
CNS metastases; and
7. Participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which
TAK-788 is active, without active CNS metastases.
The extension phase will evaluate efficacy of TAK-788 in participants with locally advanced
or metastatic NSCLC whose tumors harbor EGFR exon 20 insertion mutations and who have been
previously treated. The study will enroll approximately 395 participants.
General Inclusion Criteria all cohorts: dose escalation, antidiarrhea prophylaxis, dose
escalation combination, expansion, and extension:
1. Have histologically or cytologically confirmed locally advanced (and not a candidate
for definitive therapy) or metastatic NSCLC disease (Stage IIIB or IV) or other solid
tumors. For all cohorts except Expansion Cohort 7, the locally advanced or metastatic
disease is NSCLC. For Expansion Cohort 7, the locally advanced or metastatic disease
is any solid tumor other than NSCLC.
2. Must have sufficient tumor tissue available for analysis.
3. Must have measurable disease by response evaluation criteria in solid tumors (RECIST)
v1.1.
4. Male or female adult participants (aged 18 years or older, or as defined per local
regulations).
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
6. Minimum life expectancy of 3 months or more.
7. Adequate organ function at baseline.
8. Normal QT interval on screening electrocardiogram (ECG), defined as QT interval
corrected (Fridericia) (QTcF) of less than or equal to (<=) 450 millisecond (ms) in
males or <=470 ms in females.
9. Willingness and ability to comply with scheduled visits and study procedures.
Part 1: Dose Escalation Cohort Specific Inclusion Criteria:
1. Refractory to standard available therapies.
Part 1A: Combination dose escalation cohorts
1. Participants who have a documented EGFR activating mutation by a local test.
2. Participants with an o EGFR exon 20 insertion, with or without prior anticancer
treatments.
o EGFR mutation other than exon 20 insertions, failed or not tolerated prior
anticancer therapies.
3. Prior EGFR TKIs are allowed for all participants.
Part 1B Cohort 1: Antidiarrhea prophylaxis, monotherapy
1. Have a documented EGFR in-frame exon 20 insertion by a local test,including
A763_Y764insFQEA, V769_D770insASV, D770_N771insNPG, D770_N771insSVD, H773_V774insNPH,
or any other in-frame exon 20 insertion mutation. The EGFR exon 20 insertion mutation
can be either alone or in combination with other EGFR or HER2 mutations.
2. Previously treated with one or more regimens of systemic therapy for locally advanced
or metastatic disease.
3. Prior treatment with an EGFR TKI is allowed for all participants. Part 1B Cohort 2:
Antidiarrhea prophylaxis, combination dose with chemotherapy
1. Have a documented EGFR activating mutation by a local test,including exon 20
insertions, exon 19 deletions or exon 21 L858R substitution (with or without T790M),
or an uncommon activating mutation including G719X (where X is any other amino acid),
S768I, L861Q, or L861R, more specifically.
2. Participants with an
o EGFR exon 20 insertion, with or without prior anticancer treatments.
o EGFR mutation other than exon 20 insertions, failed or not tolerated prior
anticancer therapies.
3. Prior EGFR TKIs are allowed for all participants.
Part 2: Expansion Cohort 1 Specific Inclusion Criteria:
1. Have a documented EGFR in-frame exon 20 insertion by a local test.
2. Previously treated with one or more regimens of systemic therapy for locally advanced
or metastatic disease.
3. Prior treatment with an EGFR TKI is allowed unless the participants had an objective
response and subsequent progression as assessed by the investigator or treating
physician.
Expansion Cohort 2 Specific Inclusion Criteria:
1. Have one of the following documented by a local test:
1. A HER2 exon 20 insertion;
2. An activating point mutation in HER2.
2. Previously treated with one or more regimens of systemic therapy for locally advanced
or metastatic disease.
3. With an EGFR exon 20 insertion: Prior treatment with a pan-HER TKI (example, afatinib,
neratinib, or dacomitinib) is allowed unless the participants had an objective
response and subsequent progression as assessed by the investigator or treating
physician.
Part 2: Expansion Cohort 3 Specific Inclusion Criteria:
1. Have one of the following documented by a local test:
1. An EGFR exon 20 insertion;
2. A HER2 exon 20 insertion;
3. An activating point mutation in HER2. 2. Previously treated with one or more regimen
of systemic therapy for locally advanced or metastatic disease.
3. For participants with an EGFR exon 20 insertion: prior treatment with an EGFR TKI
is allowed unless the participants had an objective response and subsequent
progression as assessed by the investigator or treating physician.
4. For participants with a HER2 exon 20 insertion or HER2 activating point mutation:
prior treatment with a pan-HER TKI (example, afatinib, neratinib, or dacomitinib) is
allowed unless the participants had an objective response and subsequent progression
as assessed by the investigator or treating physician during treatment with that prior
TKI.
5. Have either previously untreated intracranial CNS metastases or previously treated
intracranial CNS metastases with radiologically documented new or progressing CNS
lesions.
6. Have at least one target (that is, measurable) intracranial CNS lesion (greater
than or equal to [>=]10 millimeter [mm] in longest diameter by contrast enhanced
magnetic resonance imaging [MRI]).
Part 2: Expansion Cohort 4 Specific Inclusion Criteria:
1. Have one of the following documented by a local test: an activating mutation in
EGFR including exon 19 deletions or exon 21 L858R substitution (with or without
T790M), or an uncommon activating mutation other than exon 20 insertion
including, but not limited to, G719X (where X is any other amino acid), S768I,
L861Q, or L861R.
2. Treatment naive for locally advanced or metastatic disease or previously treated
with one or more regimens of systemic therapy for locally advanced or metastatic
disease.
Part 2: Expansion Cohort 5 Specific Inclusion Criteria:
NSCLC participants with EGFR exon 20 activating insertions, who have previously shown
an objective response to an EGFR TKI and subsequently progressed, without active CNS
metastases.
1. Have a documented EGFR in-frame exon 20 insertion by a local test. 2. Previously
treated with one or more regimens of systemic therapy for locally advanced or
metastatic disease.
3. Previously showed an objective response to an EGFR TKI, and subsequently progressed
as assessed by the investigator or treating physician.
Part 2: Expansion Cohort 6 Specific Inclusion Criteria:
NSCLC participants with EGFR exon 20 activating insertions, who have not received
prior systemic anticancer treatment for locally advanced or metastatic disease,
without active CNS metastases.
1. Have a documented EGFR in-frame exon 20 insertion by a local test.
2. No prior systemic treatment for locally advanced or metastatic disease.
Part 2: Expansion Cohort 7 Specific Inclusion Criteria:
Participants with solid tumors other than NSCLC with EGFR/HER2 mutations against which
TAK-788 is active, without active CNS metastases.
1. Have a solid tumor that is not NSCLC, including, but not limited to,
bladder/urinary tract cancer, breast cancer, gastric/esophageal cancer, biliary tract
cancer, and head and neck cancer.
2. Is refractory to standard therapy. 3. Have EGFR or HER2 mutations, documented by a
local test.
Part 3: Extension Cohort Specific Inclusion Criteria:
1. Have a documented EGFR in-frame exon 20 insertion by a local test and sufficient
tumor tissue available for central analysis.
2. Must have received at least 1 prior line of therapy for locally advanced or
metastatic disease and no more than 2 regimens of systemic anticancer chemotherapies
for locally advanced or metastatic disease.
o Prior treatment with an EGFR TKI is allowed unless the participant had an objective
response and subsequent progression as assessed by the investigator or treating
physician during treatment with that prior TKI.
Exclusion Criteria:
1. Previously received TAK-788.
2. Received small-molecule anticancer therapy (including cytotoxic chemotherapy, and
investigational agents, <=14 days prior to first dose of TAK-788 (except for
reversible EGFR TKIs [that is, erlotinib or gefitinib], which are allowed in the
dose escalation and expansion cohorts up to 7 days prior to the first dose of
TAK-788).
3. Received antineoplastic monoclonal antibodies including immunotherapy within 28
days of the first dose of TAK-788.
4. Have been diagnosed with another primary malignancy other than NSCLC except for
adequately treated non-melanoma skin cancer or cervical cancer in situ;
definitively treated non-metastatic prostate cancer; or participants with another
primary malignancy who are definitively relapse-free with at least 3 years
elapsed since the diagnosis of the other primary malignancy.
Note: This exclusion criteria does not apply to Expansion Cohort 7. 5. Received
radiotherapy <=14 days prior to the first dose of TAK-788 or has not recovered from
radiotherapy-related toxicities. Palliative radiation administered outside the chest
and brain, stereotactic radiosurgery (SRS), and stereotactic body radiotherapy are
allowed up to 7 days prior to the first dose 6. Received a moderate or strong CYP4503A
inhibitor or moderate or strong CYP3A inducer within 10 days prior to first dose of
TAK-788.
7. Have undergone major surgery within 28 days prior to first dose of TAK-788. Minor
surgical procedures, such as catheter placement or minimally invasive biopsy, are
allowed.
8. Part 1 (dose escalation), Part 1A (dose escalation combination), Part 1B
(antidiarrheal prophylaxis) and Expansion Cohorts 1 to 3 of Part 2 (expansion phase)
only: Have symptomatic CNS metastases at screening or asymptomatic disease requiring
corticosteroids to control symptoms within 7 days prior to the first dose of TAK-788.
Part 3 (extension cohort) and Expansion Cohorts 4 to 7 of Part 2 (expansion phase)
only:
Have known active brain metastases (have either previously untreated intracranial 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 the first dose of TAK-788,
and have no evidence of new or enlarging brain metastases.
9. Have current spinal cord compression (symptomatic or asymptomatic and detected by
radiographic imaging) or leptomeningeal disease (symptomatic or asymptomatic).
10. Have significant, uncontrolled, or active cardiovascular disease. 11. Have a known
history of uncontrolled hypertension. Participants with hypertension should be under
treatment on study entry to control blood pressure.
12. Have prolonged QTcF interval, or being treated with medications known to be
associated with the development of Torsades de Pointes.
13. Have an ongoing or active infection, including but not limited to, the requirement
for intravenous (IV) antibiotics, or a known history of human immunodeficiency virus
(HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Testing is not required in
the absence of history.
14. Currently have or have a history of interstitial lung disease, radiation
pneumonitis that required steroid treatment, or drug-related pneumonitis.
15. Female participants who are lactating and breastfeeding or have a positive urine
or serum pregnancy test during the screening period.
Note: Female participants who are lactating will be eligible if they discontinue
breastfeeding. 16. Have gastrointestinal illness or disorder that could affect oral
absorption of TAK-788.
17. Have any condition or illness that, in the opinion of the investigator, might
compromise participant safety or interfere with the evaluation of the safety of the
drug.
Part 1A: Combination dose escalation cohorts
1. Have a history of or suspected severe hypersensitivity reaction to
platinum-containing drugs, pemetrexed, or any known excipients of these drugs.
2. Grade >2 peripheral neuropathy National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE version 5.0).
3. Have any condition or illness that, in the opinion of the investigator, would
compromise patient safety or interfere with evaluation of the study drug; this
should include known contraindications mentioned in the United States prescribing
information (USPIs) for pemetrexed, and carboplatin.
4. Received a live vaccine within 4 weeks before randomization (per USPIs for
pemetrexed and carboplatin).
Part 1B Cohort 1: Antidiarrhea prophylaxis, monotherapy 1. In addition to the
uncontrolled, or active cardiovascular disease, restrictions above; cardiac ejection
fraction less than (<) 50% by echocardiogram or MUGA scan.
Part 1B Cohort 2: Antidiarrhea prophylaxis, combination dose with chemotherapy
1. Grade >2 peripheral neuropathy
2. Received a live vaccine within 4 weeks before randomization (per USPIs for
pemetrexed and carboplatin).
3. In addition to the uncontrolled, or active cardiovascular disease, restrictions
above; cardiac ejection fraction less than (<) 50% by echocardiogram or MUGA
scan.
