A Phase 3, Open-Label, Randomized, Multi-Center Study of DZD9008 versus Platinum-Based Doublet Chemotherapy as First-Line Treatment for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertion Mutation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Cell Physiological Phenomena [G04]

Trial duration

26 Sep 2023 → ongoing

Decision date (initial)

2023-12-28

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

ORG-100034277

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Safety, Diagnosis, Therapy, Pharmacogenomic

To assess the anti-tumor efficacy of DZD9008 versus platinum-based doublet chemotherapy in participants with newly diagnosed or treatment naïve NSCLC carrying EGFR Exon20ins

Secondary objectives 5

1. 1. To further assess the anti-tumor efficacy of DZD9008 versus platinum-based doublet chemotherapy using other parameters.
2. 2. To characterize the safety and tolerability of DZD9008 versus platinum-based doublet chemotherapy.
3. 3. To assess pharmacokinetics (PK) of DZD9008 and metabolite(s) in participants receiving DZD9008
4. 4. To confirm EGFR Exon20ins mutation status in tumor tissue by central laboratory, and support the development of tumor tissue-based companion diagnostics for DZD9008
5. 5. To retrospectively assess EGFR Exon20ins mutation status in plasma ctDNA by central laboratory, and support the development of liquid biopsy companion diagnostics for DZD9008

Conditions and MedDRA coding

Locally Advanced or Metastatic Non-Small Cell Lung Cancer Harboring Epidermal Growth Factor Receptor Exon 20 Insertion Mutation

Study design 1 period

Regulatory references

Scientific advice from competent authorities

Food And Drug Administration

Plan to share IPD

No

IPD plan description

Not available

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. 1. Be able to understand the nature of the trial and provide a signed and dated, written informed consent form (ICF) prior to any study specific procedures, sampling and analyses. If a participant declines to participate in any optional exploratory research, there will be no penalty or loss of benefit to the participant, and he/she will not be excluded from other aspects of the study.
2. 2. Aged at least 18 years old (or per local regulatory/IRB requirement).
3. 3. Histologically or cytologically confirmed diagnosis of non-squamous NSCLC, locally advanced (Stage IIIB and IIIC according to the 8th edition of the AJCC TNM staging criteria) or metastatic (Stage IV), not suitable for curative therapy.
4. 4. Have written documentation of EGFR Exon20ins mutation in tumor tissue from a local CLIA-certified laboratory (or equivalent) or Sponsor designated central laboratory.
5. 5. An adequate amount* of archived tumor tissue or fresh biopsy (if archived tissue is not available) must be available prior to the study entry for EGFR Exon20ins mutation confirmation in Sponsor designated central laboratory and for supporting the development of tumor tissue-based companion diagnostics for DZD9008.
6. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at ICF signature with no deterioration over the previous 2 weeks and a predicted life expectancy ≥ 12 weeks.
7. 7. Participants with brain metastasis (BM) can be enrolled under the condition that BM is previously treated and stable, e.g., no evidence of progression for at least 2 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 the participants have received surgery or radiotherapy for their BM, a time window of 2 weeks is required prior to the randomization to ensure that the surgery- and radiotherapy-related toxicities are ≤ CTCAE grade 1.
8. 8. Participants should be newly diagnosed or have not received prior systemic treatment for locally advanced or metastatic NSCLC. Note: Patients who have received (neo)adjuvant therapy are allowed to participate in the study, if the (neo)adjuvant therapy is administrated at least 6 months prior to the diagnosis of locally advanced or metastatic NSCLC.
9. 9. Participants 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. When a participant only has post-radiotherapy lesions which have progressed with radiological evidence and are measurable, a post-radiotherapy lesion can be selected as a target lesion, Intracranial lesions should not be selected as target lesions.
10. 10. Adequate hematopoietic and other organ system functions, as outlined in the protocol
11. 11. Male participants with female partners of child-bearing potential should use barrier contraceptives (i.e., by use of condoms), during their participation in this study and for 6 months following the last dose of the study drug. Male participants must refrain from donating sperm during their participation in the study and for 6 months following the last dose of the study drug. If male participants wish to father children, they should be advised to arrange for freezing of sperm samples prior to the start of study treatment.
12. 12. Females of child-bearing potential should use reliable contraceptives from the time of screening until 6 weeks after discontinuation of study treatment. Female participants should not be breast feeding and must have a negative pregnancy test prior to start dosing or must fulfil one of the following criteria at screening: Post-menopausal defined as aged more than 50 years and amenorrhea for at least 12 months following cessation of all exogenous hormonal treatment; Women under 50 years old would be considered postmenopausal if they have been amenorrheic for ≥ 12 months following cessation of exogenous hormonal treatments and with Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) levels in the post-menopausal range; Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation

Exclusion criteria 16

1. 1. Prior treatment with any of the following: Prior treatment with any systemic anti-cancer therapy for locally advanced or metastatic NSCLC; Prior treatment with any EGFR Exon20ins inhibitors, including poziotinib, mobocertinib, CLN-081, furmonertinib, etc. or prior treatment with third generation of EGFR TKI, including but not limit to Osimertinib, Almonertinib, etc.; Participants are currently receiving or unable to stop drug or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 (CYP)3A4. A washout period of at least 1 week for strong inhibitors and 2 weeks for strong inducers, is required prior to receiving the first study drug administration; Major surgery within 4 weeks of the first study drug administration.
2. 2. Spinal cord compression or leptomeningeal metastasis.
3. 3. Concurrent EGFR mutations: exon 19 deletion, L858R, T790M, G719X, S768I, or L861Q.
4. 4. Any malignancy within 2 years of first administration of study drugs (excluding adequately treated Basal cell carcinoma or in situ cervical cancer with a tumor-free period of more than 2 years and a life expectancy of more than 2 years. Inclusion of such patients should be discussed with the study physician from Dizal Pharma).
5. 5. Any unresolved toxicities from prior anti-cancer therapy (e.g., adjuvant chemotherapy, radiation therapy) greater than CTCAE grade 1 at the time of starting study drug with the exception of CTCAE grade 2 alopecia.
6. 6. History of stroke or intracranial hemorrhage within 6 months before randomization.
7. 7. As judged by the investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses (i.e., hemophilia and Von Willebrand disease).
8. 8. Participants with active infection including but not limited to hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) (refer to below table) and active infection of COVID-19 (clinical significance as judged by investigator, with signs or symptoms, etc). The testing on COVID-19 will follow local practice.
9. 9. Any of the following cardiac criteria: Mean resting corrected QT interval (QTcF) > 470 msec obtained; 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, except medication well-controlled; History of severe and uncontrolled cardiovascular disease (e.g., myocardial infarction, unstable angina, congestive heart failure, and inadequately controlled cardiac arrhythmias with medication) within 6 months before signing the ICF.
10. 10. 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, immunotherapy induced immune-related pneumonitis.
11. 11. 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.
12. 12. Received a live vaccine within 2 weeks before randomization.
13. 13. Women who are pregnant or breast feeding.
14. 14. Hypersensitivity to active or inactive excipient of DZD9008, pemetrexed, or carboplatin.
15. 15. Involvement in the planning and conduct of the study (applies to Dizal staff or staff at the study site).
16. 16. Judgement by the investigator that the participant is unlikely to comply with study procedures, restrictions or requirements.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Progression Free Survival (PFS) as assessed by Blinded independent Central Review (BICR) per RECIST 1.1

Secondary endpoints 5

1. 1. OS (key secondary endpoint); PFS assessed by Investigator assessment per RECIST 1.1; Confirmed ORR, DoR, DCR, and percentage of tumor size change assessed by BICR and Investigator per RECIST 1.1
2. 2. AE/SAE per CTCAE 5.0; Laboratory test; Vital signs; ECG; ECHO/ MUGA scan; PFT
3. 3. Plasma concentration of DZD9008 and metabolite(s), Data from this study may form part of a pooled analysis with data from other studies.
4. 4. EGFR Exon20ins mutation status in tumor tissues, and the correlations with clinical efficacy of drugs
5. 5. EGFR Exon20ins mutation status in plasma ctDNA collected before drug medication, and the correlations with clinical efficacy of drugs

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Sponsor organisation

Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Address

No 199 Liangjing Road, Zhangjiang Hi Tech Park Pudong Zhangjiang Hi Tech Park Pudong

City

Shanghai

Postcode

201203

Country

China

Scientific contact point

Organisation

Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Contact name

Yuanli Dong

Public contact point

Organisation

Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Contact name

Donghong Liu

Third parties 15

Sponsor responsibilities

Article 77 compliance

Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Contact point sponsor

Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Article 77 implementation

Dizal (Jiangsu) Pharmaceutical Co. Ltd.

Locations

9 EU/EEA countries · 68 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 65 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

30 submissions — initial application plus substantial / non-substantial modifications