IRB Study Number 24-953
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To demonstrate superiority of adjuvant Dato-DXd in combination with rilvegostomig relative to SoC by assessment of DFS using BICR, following complete tumour resection, in participants with Stage I adenocarcinoma NSCLC who are ctDNA-positive or have at least one high-risk pathological feature.
Secondary Objectives
To estimate the effectiveness of adjuvant Dato-DXd in combination with rilvegostomig relative to SoC by assessment of OS, following complete tumour resection, in participants with Stage I adenocarcinoma NSCLC who are ctDNA-positive or have at least one high-risk pathological feature.
To assess participant-reported physical function in participants treated with adjuvant Dato-DXd in combination with rilvegostomig relative to SoC, following complete tumour resection, in participants with Stage I adenocarcinoma NSCLC who are ctDNA-positive or have at least one high-risk pathological feature.
To assess participant-reported GHS/QoL in participants treated with adjuvant Dato-DXd in combination with rilvegostomig relative to SoC, following complete tumour resection, in participants with Stage I adenocarcinoma NSCLC who are ctDNA-positive or have at least one high-risk pathological feature.
To assess the PK of Dato-DXd and rilvegostomig in combination therapy and rilvegostomig monotherapy, following complete tumour resection, in participants with Stage I adenocarcinoma NSCLC who are ctDNA-positive or have at least one high-risk pathological feature.
To investigate the immunogenicity of Dato-DXd and rilvegostomig in combination therapy and rilvegostomig monotherapy, following complete tumour resection, in participants with Stage I adenocarcinoma NSCLC who are ctDNA-positive or have at least one high-risk pathological feature.
Inclusion Criteria
Age
1 Participant must be ≥ 18 years at the time of signing the ICF.
Type of Participant and Disease Characteristics
2 All races, genders, and ethnic groups are eligible for this study.
3 Newly diagnosed and previously untreated participants with clinical Stage I (tumours < 4 cm) NSCLC, classified pre-operatively based on the eighth edition of the AJCC TNM staging manual (Amin et al 2017), with no medical contradictions to surgery at the time of screening.
NOTE: A contrast-enhanced CT or MRI scan of the chest must have been done for clinical staging. For suspicious lymph nodes, a negative endobronchial ultrasound (EBUS) or mediastinoscopy is required.
It is recommended that participants undergo combined 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET) and CT scan in order to rule out detectable extrathoracic, extracranial metastasis and to assess for potential mediastinal lymph node involvement prior to surgery.
In the absence of pre-operative FDG-PET CT imaging, pre-operative contrast-enhanced CT imaging or MRI scan must cover the liver and adrenal glands.
4 Provision of pre-operative blood sample for ctDNA evaluation within 42 days prior to surgery.
Informed Consent
5 Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the Screening Part 1 ICF and Screening Part 2 ICF and in this CSP.
NOTE: Provision of signed and dated written Screening Part 1 ICF prior to any mandatory study-specific procedures and analyses is required. Before entering Screening Part 2, a separate signed and dated written ICF is required.
5.1.2 Screening Part 2 Inclusion Criteria
Participants may enter Screening Part 2 after surgery even if the results of the Screening Part 1 procedures are still pending. Participants are eligible to be randomised to the study only if all of the following Screening Part 2 inclusion criteria (6 to 22) and none of the exclusion criteria (Section 5.2) apply.
Type of Participant and Disease Characteristics
6 Histologically documented primary NSCLC of lung adenocarcinoma histology.
7 Participants with pathological Stage I (tumours < 4 cm) NSCLC, classified post-operatively on the basis of pathological criteria, based on the eighth edition of the AJCC TNM staging manual (Amin et al 2017).
NOTE: According to the eighth edition of the AJCC TNM staging manual, in nonmucinous adenocarcinomas, only the size of the invasive component should be measured to determine the tumor size.
8 Presence of at least one of the following features, as defined by a Sponsor-designated central laboratory, including:
Participants with pathological Stage IA disease:
− a documented pre-surgical ctDNA-positive result
Participants with pathological Stage IB (tumours < 4 cm) disease:
− documented pre-surgical ctDNA-positive result OR
− documented pre-surgical ctDNA-negative result AND ≥ one of the following high-risk pathological features:
(i) VPI
(ii) LVI
(iii) High-grade histology (≥ 20% high-grade patterns, including solid, micropapillary and complex glandular patterns).
9 Complete surgical resection (R0) of the primary NSCLC (resection margins are evaluated at the bronchial, venous and arterial stumps, peribronchial soft tissue, any peripheral margin near the tumour or of additionally resected tissue). Surgical resection of the primary NSCLC can occur by open thoracotomy or by video-assisted thoracic surgery (VATS) and resection can be achieved by segmentectomy, lobectomy, sleeve resection, bilobectomy. In the case of peripheral T1abN0 tumours (T≤ 2 cm), wedge resection is acceptable. Participants who underwent pneumonectomy or who require re-resection or postoperative radiation therapy (PORT), according to investigator’s judgment, are not eligible for this study.
NOTE: All gross disease must have been removed at the end of surgery, and all surgical margins must be negative for tumour. For sublobar resections, it is recommended that the surgical margin is no less than 20 mm or maximum tumour diameter. At a minimum, the surgical pathology report must include the examination of at least 3 distinct mediastinal (N2) lymph node stations, one of which is the subcarinal (level 7), and at least one N1 hilar station, sampled/dissected at the time of resection.
If there is clear documentation in the operative report of exploration of the required lymph node areas, the participant will be considered eligible if no lymph nodes are found in those areas. Participants who underwent diagnostic wedge resection followed by definitive anatomical resection within the same anesthetic procedure are eligible.
10 Unequivocal NED at post-surgical baseline radiological assessment as documented by contrast enhanced chest and abdomen CT scan (including liver and adrenal glands) and clinical examination. A brain MRI [preferred] or brain CT with IV contrast must be done prior to randomisation if not performed prior to surgery. If clinically indicated, additional scans (eg, bone scan, etc) should be performed to confirm no evidence of metastasis.
NOTE: If imaging appearance is deemed equivocal for relapse or residual tumour and pathological confirmation of those equivocal lesions is not technically feasible, the participant will be excluded. The baseline tumour assessment must be performed at least 4 weeks after surgery and prior to randomisation (ideally as close as possible to randomisation).
11 Complete recovery from surgery (including complete post-operative wound healing), per investigator’s judgement, at the time of randomisation.
NOTE: Study intervention cannot commence within 4 weeks following surgery. No more than 12 weeks may have elapsed between surgery and randomisation for participants (in case of delays in completing the central pathology assessment of pathological high-risk factors, randomisation beyond 12 weeks after surgery may be acceptable following consultation with the Study Clinical Lead).
12 Provision of acceptable post-operative tumour sample (FFPE tumour block or slides) to assess tumour EGFR mutation/ALK rearrangement status (if no pre-existing eligible local test result is available) and tumour PD-L1 expression status as defined in the Laboratory Manual and summarised in Section 8.8, prior to randomisation.
13 Known tumour PD-L1 expression status determined prospectively using the VENTANA PD-L1 (SP263) Assay by a Sponsor-designated central laboratory. NOTE: PD-L1 status must be known prior to randomisation. Participants with unevaluable results are not eligible for the study.
14 ECOG performance status of 0 or 1, with no deterioration over the previous 2 weeks prior to the first dose of study intervention.
15 Minimum life expectancy of > 6 months.
16 In participants with pathological Stage IB (tumours < 4 cm) disease only: provision of acceptable post-operative tumour sample (FFPE tumour block or slides) to assess high-risk pathological features as defined in the Laboratory Manual and summarised in Section 8.8, prior to randomisation.
17 Provision of tumour sample (FFPE tumour block or slides) appropriate for exploratory biomarker analyses as defined in the Laboratory Manual and summarised in Section 8.8, prior to randomisation.
18 Adequate bone marrow reserve and organ function within 7 days prior to randomisation defined as:
(a) Haemoglobin ≥ 9.0 g/dL (red blood cell/whole blood transfusion is not allowed within one week prior to screening assessment).
(b) Absolute neutrophil count ≥ 1.5 × 109/L (granulocyte colony stimulating factor administration is not allowed within one week prior to screening assessment).
(c) Platelet count ≥ 100 × 109/L (platelet transfusion is not allowed within one week prior to screening assessment).
(d) TBL ≤ 1.5 × ULN or ≤ 3 × ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinaemia).
(e) Except in the setting of HBV, ALT and AST ≤ 2.5 × ULN.
See Exclusion Criterion 9 for requirements in the setting of HBV.
(f) Calculated CrCL > 45 mL/min as determined by modified Cockcroft-Gault.
Males: Weight (kg) × (140 – Age [years]) = CrCL (mL/min) × 1.73 m2 72 × serum creatinine (mg/dL) Participant’s BSA (m2)
Females: Weight (kg) × (140 – Age [years]) × 0.85 = CrCL (mL/min) × 1.73 m2 72 × serum creatinine (mg/dL) Participant’s BSA (m2) Weight 19 Body weight ≥ 30 kg.
Sex and Contraceptive/Barrier Requirements
20 Male and female.
Contraceptive use by males and females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies; see Appendix G for further details.
(a) Non-sterilised male participants:
i) Use of a condom plus an additional contraceptive method or avoid intercourse from enrolment and throughout study, until at least 4 months after the last dose of Dato-DXd, and 60 days after the last dose of rilvegostomig, in addition to the female partner using a highly effective contraceptive method. See Appendix G for further details.
ii) Starting at randomization/the first dose of study intervention, male participants must not freeze or donate sperm at any time during this study and for at least 4 months after the last dose of Dato-DXd, and 60 days after the last dose of rilvegostomig. Preservation of sperm should be considered prior to randomization/the first dose of study intervention.
Follow the relevant local prescribing information or other local label for investigator’s choice of SoC chemotherapy (ICC), relating to contraception, the time limits for such precautions, and any additional restrictions.
(b) Female participants:
(i) Females not of child-bearing potential, see Appendix G for definition.
(ii) Females receiving HRT and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for females of childbearing potential if they wish to continue using HRT during the study. Otherwise, HRT must be discontinued to allow confirmation of post-menopausal status prior to randomisation; see Appendix G for further details.
(iii) Female participants of child-bearing potential must use one highly effective form of contraception or avoid intercourse from enrolment throughout study and for at least 7 months after the last dose of Dato-DXd, or 60 days after the last dose of rilvegostomig, whichever comes later; see Appendix G for further details.
(iv) Starting at the time of randomization/the first dose of study intervention, female participants must not donate, or retrieve for their own use, ova at any time during this study and for at least 7 months after the last dose of Dato-DXd, or 60 days after the last dose of rilvegostomig, whichever comes later. Preservation of ova should be considered prior to randomization/the first dose of study intervention.
(v) Follow the relevant local prescribing information or other local label for ICC, relating to contraception, the time limits for such precautions, and any additional restrictions.
21 All females of child-bearing potential must have a negative serum pregnancy test result within 72 hours prior to randomisation (for definition for females not of child-bearing potential see Appendix G).
Informed Consent
22 Provision of signed and dated written Optional Genomics Initiative Research Information and Consent Form prior to collection of samples for optional genomic initiative research that supports the Genomic Initiative (see Appendix D).
Exclusion Criteria
Type of Participant and Disease Characteristics
1 Any non-adenocarcinoma histology (including mixed adenocarcinoma with non-adenocarcinoma histologies).
2 Participants with sensitising EGFR mutation (including, but not limited to, exon 19 deletion or exon 21 L858R, exon 21 L861Q, exon 18 G719X, or exon 20 S768I mutation) and/or ALK alteration.
NOTE: Participants with unknown EGFR/ALK status will not be randomised. If local testing is not available, prospective central testing will be offered in a Sponsor-designated central laboratory. Central testing results for EGFR/ALK obtained during screening from another AstraZeneca study may be used for participants who meet the eligibility criteria for this study. Participants whose tumours harbour KRAS mutations are eligible for the study and EGFR and ALK testing for them is not required.
3 Screening Part 1 only: If participant has a documented pre-operative DLCO and/or FEV1, and the result is less than or equal to 40% of predicted value.
Medical Conditions
4 As judged by the investigator, any evidence of diseases (such as severe or uncontrolled systemic diseases, including active bleeding diseases, active infection, active ILD/pneumonitis, serious chronic gastrointestinal conditions associated with diarrhoea (eg, active inflammatory bowel disease), psychiatric illness/social situations or significant cardiac conditions), or history of allogenic organ transplant, 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.
5 History of another primary malignancy, including any known or suspected synchronous primary lung cancer, except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study intervention 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.
6 Any unresolved toxicities from prior therapy greater than CTCAE Grade 1 at the time of starting study intervention with the exception of alopecia and Grade 2 prior platinum-therapy related neuropathy.
NOTE: 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).
7 Active or prior documented autoimmune or inflammatory disorders, including inflammatory bowel disease (eg, colitis or Crohn's disease), active non-infectious skin disease (including any grade rash, urticarial, dermatitis, ulceration, or psoriasis) requiring systemic treatment, systemic lupus erythematosus, sarcoidosis, granulomatosis with polyangiitis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, 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.
− Participants with any chronic skin condition that does not require systemic therapy.
− Participants without active disease in the last 5 years prior to enrolment may be included.
− Participants with coeliac disease controlled by diet alone.
8 Clinically significant corneal disease.
9 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.
(b) Have received HBV vaccination with only anti-HBs positivity and no clinical signs of hepatitis
(c) Are HBsAg- and anti-HBc+ (ie, those who have cleared HBV after infection) and meet conditions i-iii of criterion “d” below:
(d) Are HBsAg+ with chronic HBV infection (lasting 6 months or longer) and meet conditions i-iii below:
(i) HBV DNA viral load < 100 IU/mL.
(ii) Have normal transaminase values.
(iii) Start or maintain antiviral treatment if clinically indicated as per the investigator.
NOTE: Participants with active Hepatitis A are not eligible for this study.
10 History of active primary immunodeficiency.
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, CD4+ count ≥ 350 cells/μL, 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 CD4+ count is recommended and should be performed per local SoC (eg, every 3 months) in order to determine whether the infection is controlled and whether the participant is eligible for inclusion into the study. Participants must be tested for HIV during the screening period if acceptable by local regulations or an IRB/EC.
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 radiographical findings, or tuberculosis testing in line with local practice).
14 Resting ECG with clinically abnormal findings, including, but not limited to, the mean resting corrected QT interval > 470 ms, regardless of gender, obtained from triplicate 12-lead ECGs performed at screening.
15 Uncontrolled or significant cardiac disease including:
(a) Myocardial infarction or uncontrolled/unstable angina within 6 months before randomisation.
(b) Congestive heart failure (New York Heart Association Class II to IV).
(c) Uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg).
(d) Cardiomyopathy of any aetiology
(e) 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.
(f) Known pulmonary hypertension. In cases of suspected pulmonary hypertension, a resting sPAP of ≤ 35 mmHg is required by ECHO.
16 History of non-infectious ILD/pneumonitis including radiation pneumonitis that required steroids, has current ILD/pneumonitis, or has suspected ILD/pneumonitis that cannot be ruled out by imaging at screening.
17 Has significant pulmonary function compromise, as determined by the investigator. NOTE: a DLCO test is required before randomisation for participants with prior severe and/or prior clinically significant pulmonary disorders.
18 Is currently pregnant, breastfeeding, planning to become pregnant or father children within the projected duration of the study.
NOTE: Female participants should refrain from breastfeeding from enrolment throughout the study and until at least 7 months after last dose of Dato-DXd or 60 days after the last dose of rilvegostomig whichever comes later.
Prior/Concomitant Therapy
19 Prior neoadjuvant or adjuvant treatment with any anti-cancer therapy for NSCLC (including but not limited to chemotherapy, radiotherapy, immunotherapy, or targeted therapy).
20 Prior exposure to chloroquine/hydroxychloroquine without an adequate treatment washout period of > 14 days before randomisation (see Appendix I 2).
21 Prior exposure to:
− An anti-TIGIT therapy, anti-PD-1, anti-PD-L1 therapy or an antibody targeting any other immuno-regulatory receptors or mechanisms, including combinations and combined agents.
− Therapeutic anti-cancer vaccines.
− Any regimen including ADC containing a chemotherapeutic agent targeting topoisomerase I.
− TROP2-targeted therapy.
22 Current or prior use of immunosuppressive medication within 14 days before the first dose of study intervention.
The following are exceptions to this criterion:
− Intranasal, inhaled, topical steroids or local steroid injections (eg, intra-articular injection).
− Systemic corticosteroids at physiological doses not to exceed 10 mg/day of prednisone or its equivalent.
− Steroids as premedication for hypersensitivity/infusion reactions and adverse effects of concurrent treatments.
23 Any concurrent anti-cancer treatment
NOTE: Concurrent use of hormonal therapy for non-cancer-related conditions (eg, insulin for diabetes and HRT) is allowed. Herbal or natural products intended as treatment or prophylaxis for any type of cancer that may interfere with the activity of the study intervention are also excluded, see Appendix I.
24 Receipt of live, attenuated vaccine within 30 days prior to the first dose of study intervention.
Note: Participants, if enrolled, should not receive live vaccine while receiving study intervention and up to 30 days after the last dose of study intervention. COVID-19 vaccination should not be given in the 72 hours prior to administration of the first dose of rilvegostomig.
25 Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within ≤ 4 weeks of randomisation or an anticipated need for major surgery during the study.
Prior/Concurrent Clinical Study Experience
26 Participation in another clinical study with a study intervention or investigational medicinal device administered in the last 12 months prior to the first dose of study intervention (unless the safety profile is known and 5 times the half-life of the prior IP has passed since the last dose), previous randomisation into a prior Dato-DXd or rilvegostomig study regardless of treatment assignment, or concurrent enrolment in another clinical study (unless the study is observational [non-interventional], or the participant is in the follow-up period of an interventional study).
27 Participants with a known history of severe hypersensitivity reactions to either Dato-DXd or rilvegostomig or any excipients (including but not limited to polysorbate 80) of Dato-DXd.
28 Participants with a known history of severe hypersensitivity reactions to other mAbs.
Other Exclusions
29 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
30 Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.
31 Previous randomisation in the present study.
