A Phase I/II, Open-Label, Multicenter Study to Assess the Safety, Tolerability, Pharmacokinetics and Anti-tumor Efficacy of DZD9008 in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC) with EGFR or HER2 mutation

JRCT ID: jRCT2061210046

Registered date:28/10/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: NonSmall Cell Lung Cancer
• Date of first enrollment: 12/01/2022
• Target sample size: 10
• Countries of recruitment: United States,Japan,Australia,Japan,South Korea,Japan,Taiwan,Japan,Italy,Japan,Malaysia,Japan,Chile,Japan,Spain,Japan,France,Japan,Argentina,Japan
• Study type: Interventional
• Intervention(s): DZD9008 is orally administered at 200 mg or 300 mg once daily.

Outcome(s)

• Primary Outcome: The incidence of dose-limiting toxicities (DLTs), adverse events (AEs), serious adverse events (SAEs) and abnormal laboratory test results

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: Not applicable
• Gender: Both

Include 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
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 of >= 2 weeks or >= 4 weeks respectively, 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 Gilberts 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.

Exclude 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 investigators 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.
14. Requires anticoagulation and anti-platelet therapy, i.e. with Warfarin, heparin etc.
15. History of stroke or intracranial haemorrhage within 6 months before the first administration of DZD9008.
16. In addition, the following is considered 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.

Related Information

• Primary Sponsor: Li Zheng
• Secondary ID(s): NCT03974022