Study of Datopotamab Deruxtecan (Dato-DXd) for first line treatment of patients with locally advanced or metastatic NSCLC
- Conditions
- Health Condition 1: C349- Malignant neoplasm of unspecifiedpart of bronchus or lung
- Registration Number
- CTRI/2023/05/052218
- Lead Sponsor
- AstraZeneca AB
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Open to Recruitment
- Sex
- Not specified
- Target Recruitment
- 0
Age
1. Participant must be = 18 years at the time of screening.
Type of Participant and Disease Characteristics
2. Histologically or cytologically documented NSCLC that:
a) Is Stage IIIB or IIIC disease not amenable for surgical resection or definitive chemoradiation, or Stage IV metastatic NSCLC disease at the time of randomisation who have not received prior chemotherapy or other systemic therapy for first-line Stage IIIB, IIIC or IV NSCLC. Participants who have received prior platinum-containing adjuvant, neoadjuvant, or definitive chemoradiation for early stage disease (Stage I to IIIA) are eligible, provided that progression has occurred 6 months from the last dose of checkpoint inhibitor, chemotherapy, or other systemic anti-cancer therapy.
b) Lacks sensitising EGFR tumour tissue mutation (eg, exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 S768I mutation), as well as ALK and ROS1 rearrangements.
c) Has no documented tumour genomic alteration results in NTRK, BRAF, RET, MET or any other actionable driver oncogenes for which there are locally approved and available targeted first-line therapies.
Note: Participants whose tumours harbour KRAS mutations are eligible for the study.
3. ECOG PS of 0 or 1 with no deterioration over the previous 2 weeks prior to day of first dosing.
4. FFPE tumour sample collected prior to signing of informed consent, ie, the start of screening.
5. Tumour PD-L1 status defined as TC 1%, TC 1% to 49%, or TC 50%, determined using the VENTANA PD-L1 (SP263) IHC Assay by a central laboratory. Participants with unknown central PD L1 status are not eligible for the study.
6. TROP2 biomarker status as determined retrospectively using the VENTANA TROP2 IHC QCS Assay (clinical trial assay), or prospectively once a TROP2 IHC QCS assay is validated in a CAP/CLIA laboratory. Participants with unknown central TROP2 biomarker status are not eligible for the study once prospective testing is implemented.
7. At least 1 lesion, not previously irradiated, that qualifies as a target lesion (TL) per RECIST 1.1 at baseline and can be accurately measured at baseline as 10 mm in the longest diameter (except lymph nodes, which must have short axis 15 mm) with CT or MRI and is suitable for accurate repeated measurements.
8. Adequate bone marrow reserve and organ function within 7 days before randomisation defined as:
Haemoglobin 9.0 g/dL (red blood cell/plasma transfusion is not allowed within 1 week prior to screening assessment).
Absolute neutrophil count 1.5 109/L (granulocyte colony stimulating factor administration is not allowed within 1 week prior to screening assessment).
Platelet count 100 109/L (platelet transfusion is not allowed within 1 week prior to screening assessment).
International normalised ratio/prothrombin time and either partial thromboplastin time or activated partial thromboplastin time 1.5 ULN.
TBL 1.5 ULN or 3 ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline.
ALT and AST 3 ULN (5 ULN in participants with liver metastases).
Calculated CrCL 40 mL/min as determined by Cockcroft Gault (using actual body weight).
9. Minimum life expectancy of 12 weeks.
Sex
10. Male and/or female.
Contraceptive use by men or women
Exclusion criteria
Medical conditions
1.As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases, active systemic infection (except for HBV infection or HCV infection), active interstitial lung disease (ILD) pneumonitis, serious chronic gastrointestinal conditions associated with diarrhea, psychiatric illness/social situations) or history of allogeneic organ transplant that, in the investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardize compliance with the protocol.
2.Uncontrolled arterial hypertension defined by a systolic pressure 150 mm Hg or diastolic pressure 90 mm Hg or other hypertensive cardiovascular complications despite standard medical management.
3.Refractory nausea and vomiting, chronic gastrointestinal disease, inability to swallow a formulated product, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of Lenvatinib.
4.History of another primary malignancy. Exceptions include: 1) malignancy treated with curative intent or has low potential risk for recurrence with no known active disease 5 years before the first dose of study intervention; 2) malignancy which occurred 5 years before the first dose of study intervention, is not active, and not expected to recur or be clinically relevant in the next 5 years (may be considered pending further to discussion with the study physician prior to randomization).
5.Persistent toxicities (Common Terminology Criteria for Adverse Events [CTCAE]
Grade 2) caused by previous anticancer therapy; alopecia and vitiligo are excluded toxicities. Participants with irreversible toxicity that is not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab may be included (eg, hearing loss) after consultation with the AstraZeneca study clinical lead.
6.Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the
exception of diverticulosis], systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc), autoimmune pneumonitis and autoimmune myocarditis). The following are exceptions to this criterion:
Participants with vitiligo or alopecia.
Participants with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement.
Any chronic skin condition that does not require systemic therapy
Participants without active disease in the last 5 years may be included but only after consultation with the study clinical lead.
Participants with coeliac disease controlled by diet alone.
7.History of leptomeningeal carcinomatosis.
8.Co-infection with HBV and hepatitis D virus (HDV). (The HBV infection is indicated by the presence of HBsAg and/or anti-HBcAb with detectable HBV DNA 10 IU/mL or above the limit of detection per local lab standard; HDV positive infection is indicated by the presence of anti-HDV antibodies.)
9.Known to have tested positive for human immunodeficiency virus (HIV) (positive
HIV 1/2 antibodies) or tuberculosis infection (clinical evalua
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method To demonstrate the superiority of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum based chemotherapy by assessment of PFS by BICR in first line treatment of TROP2 biomarker positive participants with locally advanced or metastatic NSCLC <br/ ><br> <br/ ><br>To demonstrate the superiority of Dato-DXd in combination with durvalumab and carboplatin relative to pembrolizumab in combination with platinum based chemotherapy by assessment of OS in first-line treatment of TROP2 biomarker positive participants with locally advanced or metastatic NSCLCTimepoint: PFS using BICR assessments according to RECIST 1.1 will be assessed at Baseline followed by every 6 weeks (± 7 days) up to Week 12, then every 9 weeks (± 7 days) up to Week 48 and then every 12 weeks (± 7 days) thereafter, relative to the date of randomisation and until RECIST 1.1 defined radiological PD plus an additional follow-up scan at least 4 weeks later <br/ ><br> <br/ ><br> <br/ ><br>
- Secondary Outcome Measures
Name Time Method