A Phase 1b/2, Study of I-DXd in Combination with Atezolizumab with or without Carboplatin in First-line ES‑SCLC

Prior treatment

• Has received prior treatment with orlotamab, enoblituzumab, or other B7-H3 targeted agents, including I-DXd.
• Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to NCI-CTCAE V5.0, Grade ≤1 or Baseline.
• Has active or uncontrolled hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization.
• Prior discontinuation of an ADC that consists of an exatecan derivative (eg, trastuzumab deruxtecan) due to treatment-related toxicities.
• Has received a live vaccine within 30 days prior to the first dose of study drug.
• Has inadequate washout period before enrolment / randomization as specified in the study protocol.
• Has clinically active brain metastases, spinal cord compression, or leptomeningeal carcinomatosis, defined as untreated and symptomatic, or requiring therapy with steroids or anticonvulsants to control associated symptoms.

Other illness

• Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses, as explained in the study protocol.
• Is on chronic steroid treatment (dose of 10 mg daily or more prednisone equivalent), except for low-dose inhaled steroids (for asthma/chronic obstructive pulmonary disease, topical steroids (for mild skin conditions), or intra-articular steroid injections.
• Has history of malignancy other than SCLC within the 3 years prior to randomization / enrolment, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, superficial gastrointestinal tract tumours, and non-muscle invasive bladder cancer curatively resected by endoscopic surgery.
• Has history of allogeneic bone marrow, stem cell, or solid organ transplant.
• Has history of hypersensitivity to the drug substances, inactive ingredients in the drug product or severe hypersensitivity reactions to other monoclonal antibodies.
• Has evidence of ongoing uncontrolled systemic bacterial, fungal, or viral infection.
• Has active or uncontrolled HIV infection. Subjects must be tested for HIV viral load during the Screening Period if acceptable by local regulations or IRBs/IECs, as explained in the study protocol.
• Has history of autoimmune disease, as explained in the study protocol.
• Has any evidence of severe or uncontrolled systemic diseases, as included in the study protocol.
• Has clinically significant corneal disease.
• Has uncontrolled or significant cardiovascular disease, as explained in the study protocol.
• All of the following indicators of ILD/pneumonitis are excluded: a. Any history of ILD/pneumonitis irrespective of steroid use, except for a history of radiation pneumonitis that did not require steroids b. Current diagnosis of ILD c. Clinical or radiographic suspicion of ILD for which the diagnosis of ILD cannot be ruled out. Radiographic findings may include presence of lung parenchymal fibrosis, combined fibrosis and emphysema (CPFE), and/or interstitial lung abnormalities such as reticular opacities, traction bronchiectasis, honeycombing, or extensive ground glass opacities.

Lab values

• Has prior or ongoing clinically relevant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the investigator’s opinion, could affect the safety of the subject; alter the absorption, distribution, metabolism, or excretion of the study drug; or confound the assessment of study results.
• Has received prior treatment with CD137 agonists or ICIs, including anti- cytotoxic T-cell lymphocyte-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies, except for atezolizumab for Cohort 1.

Other

• Is a female who is pregnant or breastfeeding or planning to become pregnant.
• Has psychological, social, familial, or logistical factors that would prevent regular follow-up.
• Has any of the following within the past 6 months: cerebrovascular accident, transient ischemic attack, or another arterial thromboembolic event.

• Sign and date the informed consent form (ICF), prior to the start of any study-specific qualification procedures.
• A male subject capable of producing sperm is eligible to participate if he agrees to the following during the intervention period and for at least the time needed to eliminate each study drug. The length of time required to continue contraception and avoid donating sperm after last dose for I-DXd/atezolizumab/carboplatin is 5/5/6 months, respectively. a. Avoid donating sperm. Note: Preservation of sperm should be considered prior to enrolment / randomization in this trial. b. Adhere to either of the following contraception methods: i. True abstinence from penile-vaginal intercourse, when this is in line with the preferred and usual lifestyle of the subject, OR ii. Uses a penile/external condom when having penile-vaginal intercourse with a non-subject of childbearing potential PLUS partner use of an additional contraceptive method, as a condom may break or leak. Contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study drugs are more stringent than the requirements above, the local label requirements are to be followed. Note: If the subject is azoospermic (vasectomized or secondary to medical cause, documented from the site personnel’s review of the subject’s medical records, medical examination, or medical history interview), no contraception is required.
• Is willing and able to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
• Adults ≥18 years or the minimum legal adult age (whichever is greater) at the time the ICF is signed.
• Has histologically or cytologically confirmed diagnosis of ES-SCLC.
• For Cohort 1, subject has received 4 cycles of 1L induction therapy with carboplatin, etoposide, and atezolizumab for ES-SCLC with ongoing CR, PR, or SD per RECIST v1.1 assessed by the investigator. For Cohort 2, subject has received no prior treatment for ES-SCLC.
• For Cohort 2, subject has at least one measurable lesion according to RECIST v1.1 on CT or MRI as assessed by the investigator.
• For Cohort 2, subject must have at least one lesion, amenable to core biopsy, and must consent to provide a pretreatment biopsy tissue sample and on-treatment biopsy.
• Has ECOG PS of ≤1 (assessed within 7 days before enrollment/randomization).
• Has adequate organ and bone marrow function within 7 days before the start of study treatment as specified in the study protocol.
• A female subject of childbearing potential (POCBP), as defined in Section 10.3.4 of the Protocol, is eligible to participate if the following conditions are met: a. Subject is not pregnant as confirmed by highly sensitive pregnancy test during Screening (within 3 days prior to enrollment/randomization) b. Subject does not breastfeed during the treatment period and for at least 8/5/6 months after last dose of I-DXd/atezolizumab/carboplatin, respectively. c. Subject agrees to adhere to a contraceptive method that is highly effective (Section 10.3.4) and agrees not to donate eggs (ova, oocytes) to others or freeze/store eggs during the treatment period and for at least the time needed to eliminate each study drug after the last dose. The length of time required to continue contraception and avoid donating/freezing eggs after last dose for IDXd/atezolizumab/carboplatin is 8/5/6 months, respectively. Preservation of eggs may be considered prior to first dose of study drug.