Phase Ib Study of the Safety of T-DXd and Immunotherapy Agents With and Without Chemotherapy in Advanced or Metastatic HER2+, Non-squamous NSCLC
- Conditions
- Locally Advanced or Metastatic Non-Small Cell Lung Cancer
- Interventions
- Registration Number
- NCT04686305
- Lead Sponsor
- AstraZeneca
- Brief Summary
DESTINY-Lung03 will investigate the safety and tolerability of trastuzumab deruxtecan in combination with Immunotherapy Agents with and without chemotherapy in patients with HER2 over-expressing non-small cell lung cancer. The efficacy will be also analyzed as a secondary endpoint.
- 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. No more patients will be enrolled in this part of the study. Part 2, expansions in the treatment naïve setting on any recommended dose level will not be initiated. The evaluation of T-DXd combination treatment with immunotherapy continues in Part 3 and Part 4, assessing T-DXd and volrustomig with carboplatin (Arm 3B) or without carboplatin (Arm 3A) and T-Dxd and rilvegostomig with carboplatin (Arm 4B) or without carboplatin (Arm 4A).
For Part 3, patients will be randomized to Arms 3A and 3B, beginning with the cohorts receiving the volrustomig starting dose (SD). A total of 6 DLT-evaluable patients will be enrolled to the SD cohorts in each arm. If the combination of T-DXd with volrustomig at the starting dose is deemed safe, a dose escalation (E1) cohort will be opened for 6 DLT-evaluable patients. Once all open dose confirmation cohorts have 6 DLT-evaluable patients, the SRC will convene to select the volrustomig RP2D to be used in the dose-expansion (DE) cohorts of each arm (n=34).
In Part 4, once a total of 6 DLT-evaluable patients/arm have been enrolled into Arm 4A and Arm 4B safety-run in (SR) cohorts and deemed safe, an additional 34 patients per arm will be enrolled in Arms 4A and 4B in dose expansion cohorts.
The target population of interest (for Part 3 and Part 4) are patients with advanced or metastatic non-small cell lung cancer measurable disease by RECIST 1.1 criteria, HER2 overexpression, ECOG PS of 0 to 1, patients who are treatment naïve for recurrent, unresectable or metastatic disease. Patients with tumors that harbor a known genomic alteration or driver for which approved therapies are available are excluded.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 244
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm 1A: T-DXd, Durvalumab and Cisplatin T-DXd T-DXd, Durvalumab and Cisplatin Arm 1A: T-DXd, Durvalumab and Cisplatin Durvalumab T-DXd, Durvalumab and Cisplatin Arm 1A: T-DXd, Durvalumab and Cisplatin Cisplatin T-DXd, Durvalumab and Cisplatin Arm 1B: T-DXd, Durvalumab and Carboplatin Durvalumab T-DXd, Durvalumab and Carboplatin Arm 3B: T-DXd, Volrustomig and Carboplatin Volrustomig Drug: T-DXd, Volrustomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig Drug: Carboplatin Carboplatin: administered as an IV infusion Arm 4A: T-DXd and Rilvegostomig T-DXd T-DXd and Rilvegostomig Drug: T-DXd, Rilvegostomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 Arm 3A: T-DXd and Volrustomig Volrustomig Drug: T-DXd and Volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig Arm 3B: T-DXd, Volrustomig and Carboplatin T-DXd Drug: T-DXd, Volrustomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig Drug: Carboplatin Carboplatin: administered as an IV infusion Arm 4B T-DXd and Rilvegostomig with Carboplatin T-DXd Drug: T-DXd, Rilvegostomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 Drug: Carboplatin Carboplatin: administered as an IV infusion Arm 4B T-DXd and Rilvegostomig with Carboplatin Carboplatin Drug: T-DXd, Rilvegostomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 Drug: Carboplatin Carboplatin: administered as an IV infusion Arm 4A: T-DXd and Rilvegostomig Rilvegostomig T-DXd and Rilvegostomig Drug: T-DXd, Rilvegostomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 Arm 4B T-DXd and Rilvegostomig with Carboplatin Rilvegostomig Drug: T-DXd, Rilvegostomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Rilvegostomig Rilvegostomig: administered as an IV infusion Other Name: Rilvegostomig, AZD2936 Drug: Carboplatin Carboplatin: administered as an IV infusion Arm 1B: T-DXd, Durvalumab and Carboplatin T-DXd T-DXd, Durvalumab and Carboplatin Arm 1C: T-DXd, Durvalumab and Pemetrexed T-DXd T-DXd, Durvalumab and Pemetrexed (Arm not initiated) Arm 1D: T-DXd T-DXd T-DXd Arm 3A: T-DXd and Volrustomig T-DXd Drug: T-DXd and Volrustomig T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig Arm 1B: T-DXd, Durvalumab and Carboplatin Carboplatin T-DXd, Durvalumab and Carboplatin Arm 1C: T-DXd, Durvalumab and Pemetrexed Durvalumab T-DXd, Durvalumab and Pemetrexed (Arm not initiated) Arm 1C: T-DXd, Durvalumab and Pemetrexed Pemetrexed T-DXd, Durvalumab and Pemetrexed (Arm not initiated) Arm 3B: T-DXd, Volrustomig and Carboplatin Carboplatin Drug: T-DXd, Volrustomig and Carboplatin T-DXd: administered as an IV infusion Other Name: DS-8201a, Trastuzumab deruxtecan Biological/Vaccine: Volrustomig Volrustomig: administered as an IV infusion Other Name: Volrustomig Drug: Carboplatin Carboplatin: administered as an IV infusion
- Primary Outcome Measures
Name Time Method Frequency of AEs and SAEs Safety and tolerability (and to determine RP2D) 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
Name Time Method Pharmacokinetics (PK) assessed by the serum concentration of T-DXd, total anti-HER2 antibody, and MAAA-1181 in all arms 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
Pharmacokinetics (PK) assessed by the serum concentration of durvalumab in study arms including T-DXd in combination with durvalumab 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
Pharmacokinetics (PK) assessed by the serum concentration of rilvegostomig in study arms including T-DXd in combination with rilvegostomig An average of approximately 20 months Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for rilvegostomig, including T- DXd in combination with rilvegostomig
The immunogenicity of T-DXd, durvalumab, volrustomig and rilvegostomig assessed by the presence of ADAs for T-DXd, durvalumab, volrustomig, or rilvegostomig 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, durvalumab or volrustomig, or rilvegostomig
Confirmed Objective Response Rate (ORR) 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
Duration of Response (DoR) 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 1.1 assessment
Disease Control Rate (DCR) 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 1.1 assessment. DCR is assessed at 6 and 12 weeks
Progression-free survival (PFS) 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 1.1 assessment
Overall survival (OS) 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
Pharmacokinetics (PK) assessed by the serum concentration of volrustomig in study arms including T-DXd in combination with volrustomig An average of approximately 20 months Individual patient data and descriptive statistics will be provided for serum concentration data at each time point for volrustomig, including T-DXd in combination with volrustomig
Trial Locations
- Locations (1)
Research Site
🇹🇷Bornova-Izmir, Turkey