| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Small Cell Lung Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Non-Small Cell Lung Cancer |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part A of the study (Phase I):
. 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 of the study (Phase II):
. To characterize the pharmacokinetics (PK) of DZD9008 following a single oral dosing and at steady state after multiple oral dosing in the fasted state, and renal excretion of DZD9008
. To evaluate the effect of food on the exposure of DZD9008 at the defined doses
. To assess preliminary anti-tumor activity of DZD9008 according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator
. To retrospectively assess anti-tumor activity of DZD9008 in patients with EGFR Exon20ins according to RECIST 1.1 by Independent Review Committee (IRC) |
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| E.2.2 | Secondary objectives of the trial |
Part A of the study (Phase I):
. To characterize the pharmacokinetics (PK) of DZD9008 following a single oral dosing and at steady state after multiple oral dosing in the fasted state, and renal excretion of DZD9008
. To evaluate the effect of food on the exposure of DZD9008 at the defined doses
. To assess preliminary anti-tumor activity of DZD9008 according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by investigator
. To retrospectively assess anti-tumor activity of DZD9008 in patients with EGFR Exon20ins according to RECIST 1.1 by Independent Review Committee (IRC)
Part B of the study (Phase II):
. To assess anti-tumor efficacy of DZD9008 using additional endpoints
. To determine the safety and tolerability of DZD9008
. To characterize the PK of DZD9008
. To assess the effect of DZD9008 on patients’ disease-related symptoms and health related quality of life (HRQoL) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Each patient must meet all of the inclusion criteria
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 or per local regulatory/IRB requirement)
3.Histological or cytological confirmed locally advanced or metastatic NSCLC. 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 enrollment for central laboratory confirmation of mutations and/or companion diagnostics development.
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 only be enrolled under the condition that BM is previously treated and stable e.g. no evidence of progression for at least 4 weeks after CNS-directed treatment as ascertained by clinical examination and brain imaging (magnetic resonance image [MRI] or computed tomography [CT] scan) during the screening period), neurologically asymptomatic and not require corticosteroid treatment. If BM has been treated with radiation or surgery, there should be a time window, e.g. ≥ 4 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 ≤ 1.5 x ULN if no liver metastases or ≤ 3 x ULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinemia) or liver metastases
•Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN if no liver involvement or ≤ 5 x ULN with liver involvement
•Creatinine ≤ 1.5 x ULN, concurrent with calculated or measured creatinine clearance ≥ 50 mL/min as calculated by the Cockcroft-Gault method
•International normalized ratio (INR) ≤ 1.5 x ULN and activated partial thromboplastin time (APTT) ≤ 1.5 x ULN; Serum amylase ≤ 1.5 x ULN and serum lipase ≤ 1.5 x ULN
9.For inclusion in the optional genetic research study, patient must provide informed consent for genetic research. If a patient declines to participate in any voluntary exploratory research and/or genetic component of the study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded from other aspect of the study.
Part A of the study (Phase I):
Dose escalation
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 prior standard therapy without preferred alternative therapy.
Dose expansion
Dose expansion cohort 1 and cohort 2: NSCLC patients with EGFR Exon20ins or HER2 Exon20ins, who have relapsed from, been refractory to or are intolerant to at least one line of prior systemic therapy.
Dose expansion cohort 3 and cohort 4: NSCLC patients with EGFR Exon20ins, who have relapsed from, been refractory to or are intolerant to at least one line of prior systemic therapy.
Dose expansion cohort 5: NSCLC patients with EGFR Exon20ins, who have not received prior systemic therapy (treatment naïve).
Dose expansion cohort 6: NSCLC patients with EGFR Exon20ins, who have recevied at least one line of prior systemic therapy, and must have relapsed from, been refractory to or intolerant to Amivantamab treatment.
Part B of the study (Phase II):
Patients must have histologically or cytologically confirmed locally advanced or metastatic NSCLC with EGFR Exon20ins which is confirmed by central laboratory using an analytically validated next generation sequencing-based assay in archived tumor samples (if a patient has more than one FFPE blocks, the most recent tissue is preferred) or any fresh tumor biopsies (if archived tumor sample is not available) prior to the study entry. Patients should have received at least 1 line, but no more than 3 lines of systemic therapy for metastatic/locally advanced disease.
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| E.4 | Principal exclusion criteria |
1.Treatment with any of the followings:
•For expansion cohorts of Part A and Part B extension cohorts: Patients who have received prior Poziotinib, TAK-788, CLN-081 or BTDX-189 or any other EGFR/HER2 exon20ins small molecule inhibitors treatment should be excluded. Other EGFR TKIs, such as gefitinib, erlotinib, osimertinib, afatinib, dacomitinb are not considered EGFR or HER2 Exon20ins small molecule inhibitors, thus prior treatment with these drugs are allowed unless the patient had an objective response and subsequent progression as assessed by the investigator or treating physician during treatment with that prior TKI, and a minimum wash-out period of 8 days (approximately 5x half-life) prior to the first administration of DZD9008 is needed.
•Treatment with EGFR or HER2 antibodies or other antibodies within 4 weeks before the first administration of DZD9008.
•Any cytotoxic chemotherapy, investigational agents or other anticancer drugs from a previous treatment regimen or clinical study within 14 days before the first administration of DZD9008.
•Major surgery (excluding placement of vascular access) within 4 weeks before the first administration of DZD9008.
•Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose, 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 the first administration of DZD9008.
•Patients currently receiving (or unable to stop using) medications known to be potent inhibitors or inducers of CYP3A within 2 weeks or 3 weeks, respectively, before the first administration of DZD9008.
•Prior treatment with any onco-immunotherapy (e.g. immune checkpoint inhibitors PD-1, PD-L1, CTLA-4) within 4 weeks before the first administration of DZD9008.
•Treatment with any investigational drug within five half-lives of the compound (or discuss with Dizal Study team)
•Treatment with herbal supplements within 1 week and unable to stop using
2.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.
3.Spinal cord compression or leptomeningeal metastasis.
4.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, human immunodeficiency virus (HIV) and COVID-19 (per local practice, suspected subjects should perform COVID-19 antigen testing). Screening for chronic condition is not required.
5.Any of the following cardiac criteria
•Mean resting corrected QT interval (QTc) > 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 > 250 msec.
•Any factors that increase the risk of QTc 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
•Prior history of atrial fibrillation within 6 months of first administration of DZD9008, except prior drug treatment related and recovered.
6.For Part B, prior malignancy within 2 years requires active treatment, except for adequately treated basal cell skin carcinoma, in situ cervical carcinoma, or other cancer type which has been disease free for > 2 years with life expectancy >2 years.
7.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
8.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
9.History of hypersensitivity to active or inactive excipients of DZD9008 or drugs with a similar chemical structure or class to DZD9008
10.Women who are pregnant or breast feeding
11.Involvement in the planning and conduct of the study (applies to Dizal staff or staff at the study site).
12.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
13.Known history of bleeding diathesis, i.e. hemophilia, Von Willebrand disease.
Due to limit of characters, please refer to the protocol for a complete list
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| E.5 End points |
| E.5.1 | Primary end point(s) |
In Part A, the primary endpoints for determining the MTD and RP2D are the incidence of dose-limiting toxicities (DLTs), adverse events (AEs), serious adverse events (SAEs) and abnormal laboratory test results. The RP2D definition will be based on integrated analysis of PK, tolerability or anti-tumor efficacy data.
In Part B, the primary endpoints for determining anti-tumor efficacy is ORR according to RECIST 1.1 by independent image review. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: around 12 months after FSI
Part B: around 8 months after LSI |
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| E.5.2 | Secondary end point(s) |
Part A of the study (Phase I):
•PK assessment includes concentrations of DZD9008 in plasma and/or urine of individual patient (secondary)
•Preliminary assessment of anti-tumor efficacy includes the objective response rate (ORR), which includes the number of CR and PR based on RECIST v1.1, disease control rate (DCR), and duration of response (DoR) (secondary)
•The effect of food on PK of DZD9008 (secondary)
•To retrospectively assess anti-tumor activity of DZD9008 in patients with EGFR Exon20ins according to RECIST 1.1 by Independent Review Committee (IRC) (secondary)
•Retrospective confirmation of EGFR or HER2 Exon20ins in archived tumor tissue or fresh tumor biopsy or plasma sample (exploratory)
•Metabolite identification (exploratory)
•Other biomarkers (exploratory)
•To explore the relationship between DZD9008 exposure and selected endpoints
Part B of the study (Phase II):
•Safety and tolerability, including adverse events (AEs), serious adverse events (SAEs) and abnormal laboratory test results (secondary)
•PK assessment includes concentrations of DZD9008 in plasma of individual patient (secondary)
•Additional anti-tumor efficacy endpoints include BOR, DOR, PFS and overall survival (OS) (secondary).
•To assess the effect of DZD9008 on patients’ disease-related symptoms and health related quality of life (HRQoL) (secondary)
•Collect and store tumor samples for diagnostics development and potential future exploratory research that may influence the development of DZD9008 (Exploratory)
•To collect and store plasma samples for EGFR Exon20ins mutation testing and necessary technical studies for liquid biopsy companion diagnostic development and approval (Exploratory)
•To collect and store blood-based samples for future exploratory research on genes/genetic aberrations that may influence response to DZD9008 treatment and/or susceptibility to DZD9008.
•Other exploratory biomarker data if needed (pEGFR or other pathway biomarker modulation in tumor tissue by DZD9008 (at defined dose[s]) (exploratory)
•To collect and store blood sample for future exploratory research into genes/genetic variation that may influence PK or response to DZD9008 (Pharmacogenetics study, exploratory).
•To explore the effect of DZD9008 treatment and disease state on health state utility by using EQ-5D-5L health state utility index based on patient reported data.
•To assess AEs of DZD9008 by using subjects reported specific CTCAE symptoms (PRO-CTCAE) and FACIT GP5 questionnaire (exploratory).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A: around 24 months after LSI of Part B
Part B: around 24 months after LSI of Part B
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Italy |
| Japan |
| Korea, Republic of |
| Spain |
| Taiwan |
| United States |
| France |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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For the overall study, the end of the study is defined as 'the last visit of
the last patient undergoing the study' |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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