A Phase III, Randomised, Open-Label, Multicentre Study of Datopotamab Deruxtecan or Docetaxel in Previously Treated TROP2-positive Advanced or Metastatic Non-squamous Non Small Cell Lung Cancer Without Actionable Genomic Alterations (TROPION-Lung17)
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 入组人数
- 400
- 试验地点
- 5
研究概览
简要总结
Overall Design Synopsis:
Brief Summary:
The purpose of this study is to measure efficacy and safety of Dato-DXd compared with docetaxel in participants with previously treated TROP2 QCS-NMR positive advanced or metastatic non-squamous NSCLC without AGA, and to assess the clinical performance of the investigational IVD device.
Study details include:
The expected study duration will be approximately 40 months from start of recruitment until the final analysis in the study.
The expected treatment and follow-up (28-day safety follow-up and survival follow-up) duration will be approximately 15 months.
The visit frequency will be every 3 weeks during treatment.
Disclosure Statement: This is a Phase III, 2arm, randomised, open label, multicentre study, assessingthe efficacy and safety of Dato DXd compared with docetaxel in participants with TROP2 QCS NMR positive advanced or metastatic non-squamous NSCLC.
Participant Population: The target population of interest in this study is restricted to participants with advanced or metastatic non-squamous NSCLC whose tumours are TROP2 QCS-NMR positive and without AGA (ie, alterations in genes with approved therapies, such as EGFR, ALK, ROS1, NTRK, BRAF, MET exon 14 skipping, KRAS G12C, HER2, or RET).
This study will enrol TROP2 QCS NMR positive participants based on results from an appropriately validated investigational TROP2 RxDx device in a Sponsor designated central laboratory. Tumour tissue testing for an absence of sensitising EGFR mutations, as well as ALK and ROS1 rearrangements, are mandatory for all participants. In addition, participants must have no known tumour genomic alteration results from tests conducted as part of standard local practice in any other actionable driver oncogenes for which there are locally approved targeted therapies. Local test results generated as part of SoC will be documented by the clinical study sites for AGA screening and enrolment decision. If local EGFR, ALK, and ROS1 testing are not available, prospective central testing will be offered in a Sponsor designated central laboratory. Central testing results from EGFR, ALK, and or ROS1 obtained during screening from another AstraZeneca study may be used for participants who meet the eligibility criteria for this study. The full list of eligibility criteria is included in Section 5.
Number of Participants: Approximately 1050 participants will be screened to randomise approximately 400 participants in a 1:1 ratio to receive either Dato DXd or docetaxel.
Note: ‘Screened’ means a participant’s, or their legally acceptable representative’s, agreement has been obtained to participate in a clinical study following completion of the informed consent process. Potential participants who are screened for the purpose of determining eligibility for the study, but are not randomised assigned in the study, are considered ‘screen failures’, unless otherwise specified by the protocol.
Study Arms and Duration:
Participants will be randomised in a 1:1 ratio to one of the following intervention groups:
Arm A: Participants in the Dato DXd group will receive 6 mg/kg Dato DXd (up to a maximum of 540 mg for patients Greater than or equal 90 kg) as intravenous (IV) infusion every 3 weeks (Q3W) on Day 1 of every 21day cycle
Arm B: Participants in the docetaxel group will receive 75 mg/m2 as IV infusion Q3W on Day 1 of every 21day cycle
Randomisation will be stratified by:
Duration of prior anti programmed death protein 1 (PD1)/anti programmed death ligand 1 (PDL1) therapy (Less than 6 months Less than or equal 182 days versus Greater than or equal 6 months Greater than or equal 183 days)
Geographical region (US, EU, Canada versus rest of world RoW)
Participants will receive study intervention until RECIST 1.1 defined radiological progression by Investigator unless there is evidence of unacceptable toxicity, or if the participant requests to stop the study treatment.
Continuing study intervention beyond RECIST 1.1 defined progression of disease (PD) is not permitted in this study.
Follow up of Participants Post discontinuation of Study Intervention:
After study intervention discontinuation, all participants will undergo an end of treatment visit (within 35 days of discontinuation) and will be followed up for safety assessments 28 plus 7 days after their last dose of study intervention (ie, the safety follow up visit). If the day of discontinuation is over 35 days from last study intervention administration, then the safety follow up visit is not needed.
Participants who have discontinued study intervention in the absence of RECIST 1.1 defined radiological progression by Investigator assessment will be followed up with tumour assessments according to the Schedule of Activities (SoA) until RECIST 1.1 defined PD or death regardless of whether or not the participant started a subsequent anti-cancer therapy, unless they have withdrawn all consent to study-related assessments.
All participants will be followed up for survival status after intervention discontinuation every 12 weeks 14 days from the date of the safety follow-up until death, withdrawal of consent, or the end of the study (ie, progression/survival follow up), as per the SoA.
In addition, participants will be followed up for time to second progression or death (PFS2) every 12 weeks 14 days after initial objective PD until second progression on subsequent treatment, death, withdrawal of consent or end of the study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 盲法
- None
入排标准
- 年龄范围
- 18.00 Year(s) 至 99.00 Year(s)（—）
- 性别
- All
入选标准
- •Inclusion criteria Participants are eligible to be included in the study only if all of the following criteria apply: 1 Participant must be Greater than or equal 18 years old (or the legal age of consent per local regulatory requirements), at the time of signing the ICF.
- •2 Has pathologically documented Stage IIIB, IIIC, or Stage IV non-squamous NSCLC without AGA at the time of randomisation (based on the American Joint Committee on Cancer, 9th Edition) and meets the following criteria for NSCLC: a_ Participants must have documented negative test results for EGFR (eg, exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 S768I mutation), ALK, and ROS1 genomic alterations.
- •Note: If test results for EGFR, ALK, and ROS1 are not available, participants are required to undergo prospective testing performed centrally for these genomic alterations in a Sponsor-designated central laboratory.
- •b_ Has no known tumour genomic alterations in NTRK, BRAF, RET, MET exon 14 skipping, KRAS G12C, HER2 or any other actionable driver oncogenes for which there are locally approved and available targeted first-line therapies.
- •c_ Note: Participants whose tumours harbour KRAS (exception G12C) mutations are eligible for the study.
- •d_ Prospectively assessed TROP2 QCS-NMR positive based on results from an appropriately validated investigational TROP2 RxDx device in a Sponsor-designated, regulatory compliant central laboratory.
- •3 Participants must have documentation of radiographic disease progression while on or after receiving the most recent treatment regimen for advanced or metastatic NSCLC.
- •4 Participants must have received PBC in combination with anti PD 1/anti-PD-L1 mAb as the only prior line of therapy or received PBC and anti-PD-1/anti-PD-L1 monoclonal antibody (in either order) sequentially as the only 2 prior lines of therapy.
- •This will include participants initially diagnosed with: (a) Metastatic NSCLC who have received: PBC in combination with anti-PD-1/anti-PD-L1 mAb as the only prior line of systemic therapy.
- •OR Received PBC and anti-PD-1/anti-PD-L1 mAbs sequentially (in either order) as the only 2 prior lines of therapy.
- •(b) Locally advanced disease who received PBC with or without radiotherapy, followed by maintenance anti PD 1/anti-PD-L1 mAbs and progressed within 12 months after completion of PBC or who has subsequently received anti PD 1/anti PD-L1 mAb therapy (with or without platinum) for recurrent disease.
- •(c) Participants initially presenting with resectable disease who received neoadjuvant and/or adjuvant PBC and anti-PD-1/anti-PD-L1 mAbs concurrently and progressed within 12 months after completion PBC or who has subsequently received anti PD 1/anti-PD-L1 mAb therapy (with or without platinum) for recurrent disease.
- •Note: Participants who received anti-PD-1/anti-PD-L1 mAbs as first-line therapy may have received the combination of PBC and anti-PD-1/anti-PD-L1 mAbs in the second line.
- •Anti-PD-1/anti-PD-L1 mAbs includes bispecific antibodies or multitargeting proteins that are directed against PD-1 or PD-L1 as one of their targets.
- •5 Must provide an acceptable FFPE tumour sample for assessment of TROP
- •The sample must be newly acquired tumour biopsy from the current disease setting (preferred) or an archival tumour sample taken less than 24 months prior to signing the ICF.
- •6 The FFPE sample must meet the requirements specified in the Laboratory Manual or Pathology Manual and summarised in Section 8.
- •7 At least one lesion not previously irradiated that qualifies as a RECIST 1.1 TL at baseline and can be accurately measured at baseline as Greater than or equal 10 mm in the longest diameter (except lymph nodes, which must have short axis Greater than or equal 15 mm) with CT or MRI and is suitable for accurate repeated measurements (see Appendix F).
- •If only one measurable lesion exists, it is acceptable to be used (as a TL) as long as it has not been previously irradiated.
- •8 ECOG PS of 0 or 1, with no deterioration over the previous 2 weeks prior to screening.
- •9 Has life expectancy Greater than or equal 3 months based on Investigator’s opinion.
- •12 Has adequate blood clotting function defined as INR/prothrombin time and either partial thromboplastin or aPTT Less than or equal 1.5 × ULN.
- •13 Contraceptive use by males and females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies 14 Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and in this CSP.
- •Other Inclusion Criteria 15 All races, gender and ethnic groups are eligible for this study.
排除标准
- •Exclusion Criteria Participants are excluded from the study if any of the following criteria apply: 1 Squamous, mixed NSCLC, or SCLC histology.
- •2 NSCLC disease that is eligible for definitive local therapy alone.
- •3 As judged by the Investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases and significant cardiac or psychological conditions), history of allogenic organ transplant, and/or substance abuse which, in the Investigator’s opinion, makes it undesirable for the participant to participate in the study or that would jeopardise compliance with the protocol.
- •4 History of another primary malignancy other than NSCLC, except for malignancy treated with curative intent with no known active disease within 3 years before randomisation and of low potential risk for recurrence.
- •Exceptions include adequately resected non melanoma skin cancer (basal cell carcinoma of the skin or squamous cell carcinoma of the skin) and curatively treated in situ disease.
- •Note: participants may be enrolled with some chronic, stable Grade 2 toxicities (defined as no worsening to Greater than Grade 2 for at least 3 months prior to randomisation and managed with SoC treatment) which the Investigator deems related to previous anti-cancer therapy, including (but not limited to): (a) Chemotherapy-induced neuropathy.
- •(c) Residual toxicities from prior immunotherapy treatment: Grade 1 or Grade 2 endocrinopathies, which may include but are not limited to hypothyroidism/hyperthyroidism, Type I diabetes, hyperglycaemia, adrenal insufficiency, or adrenalitis; and skin hypopigmentation (vitiligo).
- •Participants with irreversible toxicity that is not reasonably expected to be exacerbated by study intervention in the opinion of the Investigator may be included (eg, hearing loss).
- •6 Spinal cord compression or brain metastases, unless asymptomatic, stable, and not requiring treatment with corticosteroids or anticonvulsants for at least 7 days prior to randomisation.
- •Participants with treated brain metastases that are no longer symptomatic and who require no treatment with corticosteroids or anticonvulsants must have recovered from the acute toxic effect of radiotherapy (eg, dizziness and signs of increased intracranial pressure).
- •A minimum of 2 weeks must have elapsed between the end of brain radiotherapy and randomisation.
- •Note: A CT or MRI scan of the brain at baseline is required for all participants.
- •For those participants in whom central nervous system metastases are first discovered at the time of screening, the treating Investigator should consider delay of study treatment to document stability of central nervous system metastases with repeat imaging at least 4 weeks later (in which case, repeat of all screening activity may be required).
- •7 Leptomeningeal carcinomatosis or metastasis.
- •8 Has significant third-space fluid retention (for example ascites or pleural effusion) and is not amenable for required repeated drainage.
- •9 Clinically significant corneal disease.
- •10 Has active or uncontrolled hepatitis B or C virus infection.
- •Participants are eligible if they: a.
- •Have been curatively treated for HCV infection as demonstrated clinically and by viral serologies.
- •Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis c.
- •Are HBsAg- and anti-HBcplus (ie, those who have cleared HBV after infection) and meet conditions i-iii of criterion “d” below: d.
- •Are HBsAgplus with chronic HBV infection (lasting 6 months or longer) and meet conditions i-iii below: HBV DNA viral load Less than 2000 IU/mL.
- •Have normal transaminase values, or, if liver metastases are present, abnormal transaminases, with a result of AST/ALT Less than 3 ULN, which are not attributable to HBV infection.
- •Start or maintain antiviral treatment if clinically indicated as per the Investigator.
- •11 Known HIV infection that is not well controlled.
- •All of the following criteria are required to define an HIV infection that is well controlled: undetectable viral RNA, CD4plus count Greater than or equal 350, no history of AIDS defining opportunistic infection within the past 12 months, and stable for at least 4 weeks on the same anti-HIV medications (meaning there are no expected further changes in that time to the number or type of antiretroviral drugs in the regimen).
- •If an HIV infection meets the above criteria, monitoring of viral RNA load and CD4plus count is recommended.
- •Participants must be tested for HIV during the screening period if acceptable by local regulations or an IRB/IEC.
- •12 Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals; suspected infections (eg, prodromal symptoms); or inability to rule out infections (participants with localised fungal infections of skin or nails are eligible).
- •13 Known to have active tuberculosis infection (clinical evaluation that may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice).
- •14 Resting ECG with clinically abnormal findings per Investigator discretion.
- •15 Uncontrolled or significant cardiac disease including: a.
- •Myocardial infarction or uncontrolled/unstable angina within 6 months before randomisation.
- •Congestive heart failure (New York Heart Association Class II to IV).
- •Uncontrolled hypertension (resting systolic blood pressure Greater than 180 mmHg or diastolic blood pressure Greater than 110 mmHg).
- •Cardiac arrhythmia (multifocal premature ventricular contractions, bigeminy, trigeminy, ventricular tachycardia), which is symptomatic or requires treatment (CTCAE Grade 3), symptomatic or uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained ventricular tachycardia.
- •Participants with atrial fibrillation controlled by medication or arrhythmias controlled by pacemakers may be permitted based on the Investigator judgement with cardiologist consultation recommended.
研究者
Mr Sandeep AV
AstraZeneca Pharma India Ltd