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Phase Ib Study of the Safety of T-DXd and Durvalumab With Chemotherapy in Advanced or Metastatic HER2+ Non-squamous NSCLC (DL03)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04686305
Recruitment Status : Recruiting
First Posted : December 28, 2020
Last Update Posted : September 16, 2021
Sponsor:
Collaborator:
Daiichi Sankyo, Inc.
Information provided by (Responsible Party):
AstraZeneca

Brief Summary:
DESTINY-Lung03 will investigate the safety and tolerability of trastuzumab deruxtecan in combination with durvalumab and chemotherapy in patients with HER2 positive advanced and metastatic non-small cell lung cancer. The efficacy will be also analyzed as a secondary endpoint.

Condition or disease Intervention/treatment Phase
Locally Advanced or Metastatic Non-Small Cell Lung Cancer Drug: Trastuzumab deruxtecan Biological: Durvalumab Drug: Cisplatin Drug: Carboplatin Drug: Pemetrexed Phase 1

Detailed Description:

Part 1 is a dose escalation study by design, allowing the assessment of safety, tolerability and recommended dose levels of the combination of T-DXd and durvalumab plus cisplatin, carboplatin or pemetrexed. In part 2, expansions in the treatment naïve setting on any recommended dose level may take place to study preliminary efficacy as well.

The target population of interest are patients with advanced or metastatic non-small cell lung cancer measurable disease by RECIST criteria, HER2 overexpression, ECOG PS of 0 to 1, patients who have received 1 or 2 prior therapies for recurrent or metastatic disease (Part 1) and patients who are treatment naïve for recurrent or metastatic disease (Part 2)

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 136 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The study will consist of 2 parts:

  • Dose-escalation part and monotherapy arm (Part 1; second-line and third-line patients): The dose of T-DXd and chemotherapeutic components on Arms 1A, 1B and 1C (cisplatin, carboplatin or pemetrexed) will be modified during the dose-escalation part in order to find the RP2D. Durvalumab dose will remain fixed on the dose escalation part of the study. Arm 1D is the T-DXd monotherapy arm.
  • Dose-expansion part (Part 2; treatment naïve patients for metastatic disease): may be initiated following dose escalation at the discretion of the sponsor.

In addition to safety and tolerability, the study will also assess preliminary efficacy based upon ORR, DoR, DCR, OS, PFS among treatment groups.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib Multicenter, Open-label Dose-escalation Study to Evaluate the Safety and Tolerability of Trastuzumab Deruxtecan (T-DXd) and Durvalumab in Combination With Cisplatin, Carboplatin or Pemetrexed in First-line Treatment of Patients With Advanced or Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC) and Human Epidermal Growth Factor Receptor 2 Overexpression (HER2+) (DESTINY-Lung03)
Actual Study Start Date : March 9, 2021
Estimated Primary Completion Date : December 13, 2023
Estimated Study Completion Date : December 13, 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Durvalumab

Arm Intervention/treatment
Experimental: Arm 1A: T-DXd, Durvalumab and Cisplatin
T-DXd, Durvalumab and Cisplatin
Drug: Trastuzumab deruxtecan
T-DXd: administered as an IV infusion
Other Name: DS-8201a, T-DXd

Biological: Durvalumab
Durvalumab: administered as an IV infusion
Other Name: MEDI4736

Drug: Cisplatin
Cisplatin: administered as an IV infusion

Experimental: Arm 1B: T-DXd, Durvalumab and Carboplatin
T-DXd, Durvalumab and Carboplatin
Drug: Trastuzumab deruxtecan
T-DXd: administered as an IV infusion
Other Name: DS-8201a, T-DXd

Biological: Durvalumab
Durvalumab: administered as an IV infusion
Other Name: MEDI4736

Drug: Carboplatin
Carboplatin: administered as an IV infusion

Experimental: Arm 1C: T-DXd, Durvalumab and Pemetrexed
T-DXd, Durvalumab and Pemetrexed
Drug: Trastuzumab deruxtecan
T-DXd: administered as an IV infusion
Other Name: DS-8201a, T-DXd

Biological: Durvalumab
Durvalumab: administered as an IV infusion
Other Name: MEDI4736

Drug: Pemetrexed
Pemetrexed: administered as an IV infusion

Experimental: Arm 1D: T-DXd
T-DXd
Drug: Trastuzumab deruxtecan
T-DXd: administered as an IV infusion
Other Name: DS-8201a, T-DXd

Experimental: Arm 2A: T-DXd, Durvalumab and Cisplatin
T-DXd, Durvalumab and Cisplatin
Drug: Trastuzumab deruxtecan
T-DXd: administered as an IV infusion
Other Name: DS-8201a, T-DXd

Biological: Durvalumab
Durvalumab: administered as an IV infusion
Other Name: MEDI4736

Drug: Cisplatin
Cisplatin: administered as an IV infusion

Experimental: Arm 2B: T-DXd, Durvalumab and Carboplatin
T-DXd, Durvalumab and Carboplatin
Drug: Trastuzumab deruxtecan
T-DXd: administered as an IV infusion
Other Name: DS-8201a, T-DXd

Biological: Durvalumab
Durvalumab: administered as an IV infusion
Other Name: MEDI4736

Drug: Carboplatin
Carboplatin: administered as an IV infusion

Experimental: Arm 2C: T-DXd, Durvalumab and Pemetrexed
T-DXd, Durvalumab and Pemetrexed
Drug: Trastuzumab deruxtecan
T-DXd: administered as an IV infusion
Other Name: DS-8201a, T-DXd

Biological: Durvalumab
Durvalumab: administered as an IV infusion
Other Name: MEDI4736

Drug: Pemetrexed
Pemetrexed: administered as an IV infusion

Experimental: Arm 2D: T-DXd, Durvalumab
T-DXd, Durvalumab
Drug: Trastuzumab deruxtecan
T-DXd: administered as an IV infusion
Other Name: DS-8201a, T-DXd

Biological: Durvalumab
Durvalumab: administered as an IV infusion
Other Name: MEDI4736




Primary Outcome Measures :
  1. Frequency of AEs and SAEs [ Time Frame: Safety will be assessed for approximately 20 months from informed consent ]
    Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0


Secondary Outcome Measures :
  1. Confirmed Objective Response Rate (ORR) [ Time Frame: An average of approximately 12 months ]
    Confirmed ORR per RECIST 1.1 is the percentage of patients with Complete Response or Partial Response that is subsequently confirmed, based on investigator assessment

  2. Duration of Response (DoR) [ Time Frame: An average of approximately 20 months ]
    DOR is defined as the time from the date of first documented response until the date of documented progression or death, based on RECIST assessment

  3. Disease Control Rate (DCR) [ Time Frame: An average of approximately 12 months ]
    DCR is the percentage of patients who have a best overall response of complete response (CR) or partial response (PR) or stable disease (SD), based on RECIST assessment

  4. Progression-free survival (PFS) [ Time Frame: An average of approximately 20 months ]
    PFS is the time from first dose of study treatment until the date of objective disease progression or death, based on RECIST assessment

  5. Overall survival (OS) [ Time Frame: An average of approximately 20 months ]
    OS is the time form the date of first dose of study treatment until death due to any cause

  6. Frequency of AEs and SAEs [ Time Frame: Safety will be assessed for approximately 20 months from informed consent ]
    Occurrence of AEs and SAEs graded according to NCI CTCAE v5.0

  7. Pharmacokinetics (PK) assessed by the serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181 in all arms [ Time Frame: An average of approximately 20 months ]
    Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for T-DXd, total anti-HER2 antibody and MAAA-1181a

  8. Pharmacokinetics (PK) assessed by the serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab [ Time Frame: An average of approximately 20 months ]
    Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for durvalumab, including T-DXd in combination with durvalumab

  9. The immunogenicity of T-DXd and durvalumab assessed by the presence of ADAs for T-DXd and durvalumab [ Time Frame: An average of approximately 20 months ]
    Individual participant data and descriptive statistics will be provided for data at each time point for each dose level for T-DXd and durvalumab.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 120 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

  • Histologically documented unresectable locally advanced/metastatic non-squamous NSCLC
  • Part 1: Progression after 1 or 2 lines of systemic therapy for recurrent or metastatic setting.
  • Part 2: Treatment-naïve for non curative treatment for locally advanced or metastatic NSCLC.
  • Part 2: Patients must have tumors that lack activating EGFR mutations, EML4-ALK fusion or other targetable alterations. Prior adjuvant, neoadjuvant therapies are permitted if progression has occurred > 12 months from the end of last therapy
  • HER2+ (IHC 3+ or IHC 2+) status as determined by central review of tumor tissue
  • WHO / ECOG performance status of 0 or 1
  • Measurable target disease assessed by the investigator using RECIST 1.1
  • Has protocol defined adequate organ and bone marrow function

Exclusion criteria:

  • HER2 mutation if previously known
  • Has a history of (non-infectious) ILD/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
  • Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder and prior pneumonectomy
  • Active primary immunodeficiency known HIV infection, or active hepatitis B or C infection
  • Active infection including tuberculosis and uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
  • Spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
  • Medical history of myocardial infarction within 6 months before treatment assignment, symptomatic CHF (New York Heart Association Class II to IV), clinically important cardiac arrhythmias, or a recent (< 6 months) cardiovascular event including stroke
  • A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or CART (Concentrated Ascites Reinfusion Therapy)
  • Unresolved toxicities from previous anticancer therapy OR prior discontinuation of any planned study therapy due to toxicity.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04686305


Contacts
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Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com

Locations
Show Show 49 study locations
Sponsors and Collaborators
AstraZeneca
Daiichi Sankyo, Inc.
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Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT04686305    
Other Study ID Numbers: D967YC00001
First Posted: December 28, 2020    Key Record Dates
Last Update Posted: September 16, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.
Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
URL: https://astrazenecagroup-dt.pharmacm.com/DT/Home

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by AstraZeneca:
HER2+
DS-8201a
T-DXd
Trastuzumab Deruxtecan
Locally advanced and unresectable non-squamous NSCLC
Metastatic non-squamous NSCLC
Non-small cell lung cancer
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Carboplatin
Trastuzumab
Pemetrexed
Durvalumab
Antineoplastic Agents
Antineoplastic Agents, Immunological
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Folic Acid Antagonists
Nucleic Acid Synthesis Inhibitors