Non-Small Cell Lung Cancer

Part A (dose escalation) To investigate the safety and tolerability of DZD9008 when given orally to patients with advanced NSCLC with EGFR or HER2 mutations To establish Maximum Tolerated Dose (MTD) (if possible) and Recommended Phase 2 Dose (PR2D) of DZD9008 when given orally in patients with advanced NSCLC with EGFR or HER2 mutations Part B To evaluate anti-tumor activity of DZD9008 in advanced NSCLC patients with EGFR Exon20ins, HER2 Exon20ins or EGFR uncommon mutation at defined dose(s)

DZD9008

DZD9008

film-coated tablet

25mg, 50 mg, 100 mg, 150mg and 200mg

Primary Outcome Measures :
Part A: Safety and tolerability of DZD9008. [ Time Frame: 28 days after the first multiple dose ]
To investigate the safety and tolerability of DZD9008 when given orally to patients with advanced NSCLC with EGFR or HER2 mutations; To establish Maximum Tolerated Dose (MTD) (if possible) and Recommended Phase 2 Dose (PR2D) of DZD9008 when given orally in patients with advanced NSCLC with EGFR or HER2 mutations.

Part B: Objective Response Rate (ORR) according to RECIST 1.1. [ Time Frame: through the study completion, an average of around 1 year ]
To evaluate anti-tumor activity of DZD9008 in advanced NSCLC patients with EGFR Exon20 insertion, HER2 Exon20 insertion or EGFR uncommon mutations at defined dose(s) (Part B)


Secondary Outcome Measures :
Plasma DZD9008 concentration [ Time Frame: Through cycle 3 day 1 (8 days for Cycle 0, 28 days for Cycle 1, then 21 days for each subsequent cycle) ]
To characterize the pharmacokinetics (PK) of DZD9008 following a single oral dosing and at steady state after multiple oral dosing, and renal excretion of DZD9008

1. Patients must be able to understand the nature of the trial and provide a
signed and dated, written informed consent form prior to any study
specific procedures, sampling and analyses.
2. Aged at least 18 years old (≥ 20 if in Japan) .
3. Patients must have documented histological or cytological confirmed
locally advanced or metastatic NSCLC with EGFR or HER2 mutations
(see cohort specific inclusion criteria for details). The mutation status is
determined by molecular assays in Clinical Laboratory Improvement
Amendments (CLIA)-certified laboratories (USA sites) or other similarly
certified laboratories (outside of USA). An adequate amount of tumor
tissue (archived tumor tissue, or fresh biopsy if archived tissue is not
available) must be available at the time of enrolment for central lab
validation of mutations.
4. Patients must exhibit Eastern Cooperative Oncology Group (ECOG)
performance status 0-1 at ICF signature with no deterioration over the
previous 2 weeks.
5. Predicted life expectancy ≥12 weeks
6. Patient must have measurable disease according to RECIST 1.1: At least
one lesion, not previously irradiated, that can be accurately measured at
baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with computed tomography (CT) or
magnetic resonance imaging (MRI) and which is suitable for repeated
measurement.
7. Patients with brain metastasis (BM) can be enrolled under the condition
that BM is stable, neurologically asymptomatic and not require
corticosteroid treatment. If BM has been treated with radiation or surgery,
there should be a time window, e.g. ≥ 2 weeks, before the first dosing of
DZD9008 to ensure radiation or surgery related AEs have recovered to ≤
grade 1.
8. Adequate organ system functions, as outlined below
 Absolute neutrophil count (ANC) ≥ 1.5 x 109
/L
 Platelets ≥ 100 x 109
/L
 Hemoglobin ≥ 9 g/dL
 Total bilirubin < 1.5x ULN if no liver metastases or < 3x ULN in the
presence of documented Gilbert’s Syndrome (unconjugated
hyperbilirubinemia) or liver metastases
 Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤
2.5x ULN if no liver involvement or ≤ 5x ULN with liver involvement
 Creatinine ≤ 1.5x ULN, or calculated or measured creatinine clearance ≥ 50
mL/min as calculated by the Cockcroft-Gault method, or 24-hour measured
urine creatinine clearance ≥ 50 mL/min

Cohort specific inclusion criteria
Part A
Patients must have documented histologically or cytologically confirmed locally advanced or
metastatic NSCLC with EGFR or HER2 mutations, and have relapsed from, been refractory
to or are intolerant to at least one line of standard therapy.

Part B
 Cohort 1: Patients must have documented histologically or cytologically
confirmed locally advanced or metastatic NSCLC with EGFR Exon20
insertion determined by next generation sequencing (NGS) assays in
Clinical Laboratory Improvement Amendments (CLIA)-certified
laboratories (USA sites) or other similarly certified laboratories (outside of
USA), with or without prior systemic treatment.
 Cohort 2: Patients must have documented histologically or cytologically
confirmed locally advanced or metastatic NSCLC with HER2 Exon20
insertion determined by NGS assays in Clinical Laboratory Improvement
Amendments (CLIA)-certified laboratories (USA sites) or other similarly
certified laboratories (outside of USA), with or without prior systemic
treatment.
 Cohort 3: Patients must have documented EGFR uncommon mutation
determined by NGS assays in Clinical Laboratory Improvement
Amendments (CLIA)-certified laboratories (USA sites) or other similarly
certified laboratories (outside of USA), with or without prior systemic
treatment.
 Cohort 4: Patients must have documented EGFR or HER2 Exon20 insertion
determined by NGS assays in Clinical Laboratory Improvement
Amendments (CLIA)-certified laboratories (USA sites) or other similarly
certified laboratories (outside of USA), with or without treatment.

1. For cohort 1, 2, 4: Patients who have received prior Poziotinib or
TAK788 or other EGFR/HER2 exon20ins selective inhibitors treatment
should be excluded. Currently approved EGFR TKIs, such as gefitinib,
erlotinib, osimertinib, afatinib, dacomitinb are not considered EGFR or
HER2 exon20 insertion selective inhibitors, thus prior treatment with
these drugs are allowed.
2. Treatment with EGFR or HER2 antibodies within 4 weeks before
screening.
3. Any cytotoxic chemotherapy, investigational agents or other anticancer
drugs from a previous treatment regimen or clinical study within 14 days
before screening.
4. Major surgery (excluding placement of vascular access) within 4 weeks
before screening.
5. Radiotherapy with a limited field of radiation for palliation within 1 week
of the first dose of , with the exception of patients receiving radiation to
more than 30% of the bone marrow or with a wide field of radiation
which must be completed within 4 weeks before screening.
6. Patients currently receiving (or unable to stop using) medications or
herbal supplements known to be potent inhibitors or inducers of CYP3A
within 2-3 week before screening.
7. Grapefruit, grapefruit juice, and orange marmalade (made with Seville
oranges) should be excluded for 1 week before screening because it is a
known inhibitor of intestinal (after substantial amounts also hepatic)
CYP3A4.
8. Prior treatment with any onco-immunotherapy (e.g. immune checkpoint
inhibitors PD-1, PD-L1, CTLA-4) within 4 weeks before screening.
Other novel agents within clinical trials need to be evaluated by both
investigator and Study Physician before enrolment.
9. Any unresolved toxicities from prior therapy greater than CTCAE grade
1 at the time of starting DZD9008 with the exception of alopecia and
grade 2 prior platinum-therapy related neuropathy.
10. Spinal cord compression or leptomeningeal metastasis.
11. As judged by the investigator, any evidence of severe or uncontrolled
systemic diseases, including uncontrolled hypertension and active
bleeding diatheses, which in the investigator’s opinion makes it
undesirable for the patient to participate in the trial or which would
jeopardize compliance with the protocol, or active infection including
hepatitis B, hepatitis C and human immunodeficiency virus (HIV) .
Screening for chronic condition is not required.
12. Any of the following cardiac criteria
 Mean resting corrected QT interval (QTcF) > 470 msec obtained from 3
electrocardiograms (ECGs)
 Any clinically significant abnormalities in rhythm, conduction or
morphology of resting ECG, e.g., complete left bundle branch block, third
degree heart block, and second-degree heart block, PR interval > 250msec.
 Any factors that increase the risk of QTcF prolongation, such as heart
failure, hypokalemia, congenital long QT syndrome, family history of long
QT syndrome or unexplained sudden death under 40 years of age in first
degree relatives or any concomitant medication known to prolong the QT
interval
13. Past medical history of interstitial lung disease, drug-induced interstitial
lung disease, radiation pneumonitis which required steroid treatment, or
any evidence of clinically active interstitial lung disease
14. Refractory nausea and vomiting, chronic gastrointestinal diseases,
inability to swallow the formulated product or previous significant bowel
resection that would preclude adequate absorption of DZD9008
15. History of hypersensitivity to active or inactive excipients of DZD9008
or drugs with a similar chemical structure or class to DZD9008
16. Women who are pregnant or breast feeding
17. Involvement in the planning and conduct of the study (applies to Dizal
staff or staff at the study site).
18. Judgment by the investigator that the patient should not participate in the
study if the patient is unlikely to comply with study procedures,
restrictions and requirements
19. In addition, the following is considered a criteria for exclusion from the
exploratory genetic research:
 Previous allogenic bone marrow transplant
 Non-leukocyte depleted whole blood transfusion within 120 days of
the date of the genetic sample collection.