Non-small Cell Lung Cancer

The primary objectives are: -For Dose Escalation, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population and to determine the recommended dose for expansion of DS-1205c when combined with osimertinib in the study population -For Dose Expansion, to assess the safety and tolerability of DS-1205c when combined with osimertinib in the study population

DS-1205c

DS-1205c

Capsule

200

Dose Escalation
Primary Endpoints (ie, Primary Outcome Measures)
 To determine the safety and tolerability of DS-1205c in
combination with osimertinib, the endpoints will include
DLTs, serious adverse events (SAEs), treatment-emergent
adverse events (TEAEs), physical examination findings
(including ECOG PS), vital sign measurements,
ophthalmologic findings, standard clinical laboratory
parameters, ECG parameters (including the change-frombaseline ECG parameters: heart rate [HR]; PR; QTcF; and
QRS intervals [∆HR, ∆PR, ∆QTcF, and ∆QRS]), and ECHO
or MUGA findings. Adverse events (AEs) and abnormal
laboratory findings will be graded according to the National
Cancer Institute-Common Terminology Criteria for Adverse
Events (NCI-CTCAE) version 5.0.

Dose Expansion
Primary Endpoints (ie, Primary Outcome Measures)
 To determine the safety and tolerability of DS-1205c in
combination with osimertinib, the endpoints will include
SAEs, TEAEs, physical examination findings (including
ECOG PS), vital sign measurements, ophthalmologic
findings, standard clinical laboratory parameters, ECG
parameters (including the change-from-baseline ECG
parameters: HR; PR; QTcF; and QRS intervals [∆HR, ∆PR,
∆QTcF, and ∆QRS]), and ECHO/MUGA findings. AEs and
laboratory findings will be graded according to the
NCI-CTCAE version 5.0.

Key Inclusion Criteria:
1. Has histologically or cytologically documented
adenocarcinoma NSCLC.
2. Has locally advanced or metastatic NSCLC, not amenable to
curative surgery or radiation.
3. Has acquired resistance to EGFR TKI according to the
Jackman criteria (PMID: 19949011):
a. Historical confirmation that the tumor harbors an
EGFR mutation known to be associated with EGFR
TKI sensitivity (including G719X, exon 19 deletion,
L858R, L861Q), OR
b. Has experienced clinical benefit from an EGFR TKI, followed by systemic progression (Response
Evaluation Criteria in Solid Tumors [RECIST
version 1.1] or World Health Organization [WHO])
while on continuous treatment with an EGFR TKI.
4. Is currently receiving (at the prescribed 80 mg dose) and able
to interrupt osimertinib or discontinue erlotinib, gefitinib, or
afatinib.
5. Has been receiving erlotinib, gefitinib, afatinib, or osimertinib
for at least 6 weeks with well-controlled related toxicities less
than Grade 3 in severity at the time of screening period.
6. Has radiological documentation of disease progression while
receiving continuous treatment with erlotinib, gefitinib,
afatinib, or osimertinib.
7. Has at least one measurable lesion per RECIST version 1.1.
8. Is willing to provide archival tumor tissue from a biopsy
performed after progression during treatment with erlotinib,
gefitinib, afatinib, or osimertinib OR has at least one lesion,
not previously irradiated, amenable to core biopsy and is
willing to undergo screening tumor biopsy.
9. Demonstrates absence of EGFR T790M. No EGFR mutation
testing is required if treated with osimertinib.
10. Has Eastern Cooperative Oncology Group (ECOG)
performance status (PS) of 0 or 1, with no deterioration over
the previous 2 weeks.

Key Exclusion Criteria:
1. Has any evidence of small cell histology, or combined small
cell and non-small cell histology, in original tumor biopsy or
in screening biopsy performed since progression.
2. Has previously documented evidence of anaplastic lymphoma
kinase (ALK) fusion, ROS proto-oncogene 1 (ROS1) fusion,
BRAF V600E mutation, rearranged during transfection (RET)
rearrangement, human epidermal growth factor receptor 2
(HER2) mutation, or MET exon 14 skipping mutation. No
new testing for these genomic alterations is required for
Screening.
3. Has received treatment with any of the following:
a. Any cytotoxic chemotherapy, immune checkpoint
inhibitor therapy, investigational agent or other
anticancer drug(s) from a previous cancer treatment
regimen or clinical study (other than EGFR TKI),
within 14 days of the first dose of study treatment.
b. Immune checkpoint inhibitor therapy within 30 days
of first dose of study treatment.
c. Major surgery (excluding placement of vascular
access) within 4 weeks of the first dose of study
treatment.
d. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4
weeks, or palliative radiation therapy within 2 weeks
of the first dose of study drug treatment.
4. Has history of other active malignancy within 3 years prior to
enrollment, except:
a. Adequately treated non-melanoma skin cancer OR
b. Superficial bladder tumors (tumor stage “a” [Ta],
tumor stage “is” [Tis], tumor stage “1” [T1]) OR
c. Curatively treated in situ disease OR
d. Low risk non-metastatic prostate cancer (with
Gleason score  7, and following local treatment or
undergoing active surveillance)
5. Has spinal cord compression or clinically active brain
metastases, defined as untreated and symptomatic, or
requiring therapy with corticosteroids or anticonvulsants to
control associated symptoms. Subjects with clinically
inactive brain metastases may be included in the study.
Subjects with treated brain metastases that are no longer
symptomatic and who require no treatment with
corticosteroids or anticonvulsants may be included in the
study if they have recovered from the acute toxic effect of
radiotherapy. A minimum of 2 weeks must have elapsed
between the end of whole brain radiotherapy and study
enrollment (1 week for stereotactic radiotherapy).
6. Presence of retinal disease in the eye that is not due to
neovascular age-related macular degeneration (nAMD; eg,
significant diabetic retinopathy, glaucomatous retinal atrophy,
retinal detachment).
7. Has history of myocardial infarction within the past 6 months.
8. Has symptomatic congestive heart failure (New York Heart
Association [NYHA] Classes II–IV), unstable angina, or
cardiac arrhythmia requiring antiarrhythmic treatment.
9. Has left ventricular ejection fraction (LVEF) <45% by either
echocardiogram (ECHO) or multigated acquisition (MUGA)
scan.
10. Has any clinically important abnormalities in rhythm,
conduction or morphology of resting ECG, eg, complete left
bundle branch block, third-degree heart block, second-degree
heart block, or PR interval >250 milliseconds (ms).
11. Has a mean QT interval corrected using Fridericia’s
correction (QTcF) prolongation >470 ms for females and
>450 ms for males in three successive Screening
measurements.
12. Unable or unwilling to discontinue concomitant use of drugs
that are known to prolong the QT interval.
13. Has any factors that increase the risk of QTc prolongation or
risk of arrhythmic events, such as congenital long QT.
syndrome, family history of long QT syndrome or
unexplained sudden death under 40 years of age in
first-degree relatives.
14. Has any history of interstitial lung disease (pulmonary fibrosis
or severe radiation pneumonitis) or is suspected to have such
disease by imaging during screening.
15. Has history of pancreatitis within the past 6 months.