IRB Study Number 25-184
Status Recruiting
Phase Phase 3
Location Mercy Hospital
Institute Taussig Cancer Institute
Description
Primary Objectives
To compare the efficacy of I-DXd with that of TPC, as measured by ORR per BICR and OS, in subjects with relapsed SCLC
Secondary Objectives
To further evaluate the efficacy of I-DXd compared with TPC in subjects with relapsed SCLC
To evaluate HEOR endpoints, including patient-reported quality of life captured via PRO measures, for I-DXd compared with TPC in subjects with relapsed SCLC
To evaluate the safety and tolerability of I-DXd with that of TPC in subjects relapsed SCLC
To assess the immunogenicity of I-DXd (only for subjects randomized to the I-DXd group)
To evaluate B7-H3 protein expression in tumor tissue and its relationship with clinical efficacy outcome
To characterize the PK of I-DXd (only for subjects randomized to the I-DXd group)
Inclusion Criteria
Sign and date the ICF prior to the start of any study-specific qualification procedures.
Adults ≥18 years or the minimum legal adult age (whichever is greater) at the time the ICF is signed.
Has histologically or cytologically documented ES-SCLC.
The subject must provide adequate baseline tumor samples with sufficient quantity and quality of tumor tissue content. Required tumor tissue can be provided as one of the following:
a. If medically feasible, newly obtained pretreatment tumor biopsy from at least 1 lesion amenable to biopsy
b. If the tumor is inaccessible or the subject is medically unfit for collection of the pretreatment tumor biopsy, archival tumor tissue collected from a biopsy performed within 6 months of consent and performed after treatment with their most recent anticancer therapy regimen.
c. If the newly obtained pretreatment biopsy is not feasible or the procedure is unsuccessful and an appropriate archival sample (ie, collected within 6 months prior to study consent and performed after treatment with their most recent anticancer therapy regimen) is not available, an archival tumor biopsy from initial diagnosis. If, after all efforts have been made, no qualifying tumor tissue is available, the subject may be considered for study eligibility at the investigator’s discretion after discussion with the Sponsor medical monitor.
Has received prior therapy with only one prior platinum-based line as systemic therapy for SCLC with at least 2 cycles of therapy and a chemotherapy-free interval of ≥30 days. Subjects with or without prior immune-checkpoint inhibitor therapy are eligible. Subjects treated with a platinum-based line of therapy for prior LS-SCLC may be eligible for the study if the disease has progressed on treatment or within 6 months from platinum treatment completion: the platinum-based line of therapy will count as 1L of therapy. If the investigator believes a subject may benefit from platinum rechallenge, such subject may not participate in the study. Subjects must not have received more than one prior line of systemic therapy. One line of therapy will be defined as 1 or more drugs received prior to newly documented disease progressions. Any switch between carboplatin and cisplatin for toxicity reasons will be regarded as one line overall.
Has at least 1 measurable lesion according to RECIST v1.1 as assessed by the investigator. Measurable lesions should not be from a previously irradiated site. If the lesion at a previously irradiated site is the only selectable target lesion, a radiological assessment showing significant progression of the irradiated lesion should be provided by the investigator.
Has documentation of radiological disease progression on or after the most recent systemic therapy.
Has ECOG PS of ≤1 within 7 days prior to C1D1.
Has no evidence of brain or leptomeningeal disease (spinal cord or CNS metastases) based on history and physical examination. For subjects with evidence of brain or leptomeningeal disease, they may be eligible if condition has been treated and a lack of progression within 4 weeks prior to initiation of study drug has been radiologically documented. Subjects must require no treatment with steroids or anticonvulsants and have a stable neurologic status for at least 2 weeks prior to the first dose of study drug. Subjects with untreated brain metastases will be allowed if they are asymptomatic, the investigator determines there is no immediate CNS-specific treatment required, there is no significant surrounding edema, and the brain metastases are of 5 mm or less in size and 3 or fewer. Note: A baseline magnetic resonance imaging scan or computed tomography of the brain is required for all subjects at baseline.
Has adequate organ and bone marrow function within 7 days before the start of study treatment. Transfusion (red blood cell or platelet) or granulocyte-colony stimulating factor administration is not allowed within 2 weeks prior to screening laboratory tests. Whenever the local label of the TPC agent to be selected has stricter criteria in laboratory values for starting the study drug, this should be considered. Adequate organ and bone marrow function is defined as:
a. Platelet count ≥100 × 109/L
b. Hemoglobin ≥9.0 g/dL
c. Absolute neutrophil count ≥1.5 × 109/L
d. Creatinine clearance ≥30 mL/min, as calculated using the Cockcroft-Gault equation
e. Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤3 × upper limit of normal (ULN) in subjects with no liver metastasis or ≤5.0 × ULN in subjects with liver metastasis
f. Total bilirubin ≤1.5 × ULN if no liver metastases or ≤3 × ULN in the presence of documented Gilbert’s syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline
g. International normalized ratio/prothrombin time and either partial thromboplastin time or activated partial thromboplastin time ≤1.5 × ULN, except for subjects receiving anti-vitamin K derivative anticoagulant therapy who must have prothrombin time-international normalization ratio within the therapeutic range as deemed appropriate by the investigator.
- POCBP, as defined in Section 10.3.4.1, is eligible to participate if the following conditions are met:
a. Subject is not pregnant as confirmed by highly sensitive pregnancy test (see Section 10.3.4.3) during Screening (within 3 days prior to randomization).
b. Subject does not breastfeed during the treatment period and for at least 8 months after last dose of I-DXd, for at least 2 weeks after last dose of topotecan, and for at least 4 weeks after the last dose of lurbinectedin. Breastfeeding precautions for subjects receiving amrubicin should follow locally approved label.
c. –Subject agrees to adhere to a contraceptive method that is highly effective (Section 10.3.4.2) 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 the last dose of study drug is at least 8 months for I-DXd, at least 6 months for topotecan, and at least 7 months for lurbinectedin. POCBP receiving amrubicin must be willing to use a highly effective birth control and avoid donating/freezing eggs in compliance with locally approved label. Preservation of eggs may be considered prior to enrollment/randomization in this study.
d. A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in female subjects who are not using hormonal contraception or HRT. In the absence of 12 months of amenorrhea, confirmation with 2 FSH measurements in the postmenopausal range is required.
- A male subject capable of producing sperm is eligible to participate if he agrees to the following during the treatment 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 of study drug is at least 6 months for I-DXd, at least 3 months for topotecan, and at least 4 months for lurbinectedin. Male subjects receiving amrubicin must be willing to use a highly effective birth control and avoid donating sperm in compliance with the study drug locally approved label.
a. Avoid donating sperm. Note: Preservation of sperm should be considered prior to enrollment/randomization in this study.
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 NPOCBP (see Section 10.3.4.1) PLUS partner use of an additional contraceptive method (see Section 10.3.4.2), as a condom may break or leak.
c. 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 (including patient-reported outcomes [PROs]), and study restrictions.
Exclusion Criteria
Has received prior treatment with orlotamab, enoblituzumab, or other B7-H3 targeted agents, including I-DXd.
Prior discontinuation of an ADC that consists of an exatecan derivative (eg, trastuzumab deruxtecan) due to treatment-related toxicities.
Has received any of the comparators used in this study or any topoisomerase I inhibitor. Subjects who received any of the TPC options except topotecan as 1L therapy may be eligible, provided that a different TPC option from the one given as prior therapy is administered (TPC cannot be repeated). The subject should not present any formal contraindication for the remaining TPC.
Has inadequate washout period before randomization, defined as follows:
a. Major surgery (placement of vascular access will not be regarded as a major surgery) <4 weeks; surgery for low-invasive cases (eg, colostomy) <2 weeks.
b. Radiation therapy <4 weeks; palliative stereotactic radiation therapy without abdominal radiation ≤2 weeks; radiation therapy to the lung >30 Gy <6 months; palliative radiotherapy affecting lung areas at lower dose <3 weeks; cranial irradiation, including whole brain radiation therapy and stereotactic radiosurgery ≤2 weeks.
c. Any systemic anticancer therapy (including immunotherapy [other than antibodies] and investigational drugs) <3 weeks or 5 half-lives, whichever is longer; hormonal therapy (except for luteinizing hormone-releasing hormone agonists/antagonists) <2 weeks.
d. Antibody-based anticancer therapy <3 weeks.
e. Chloroquine or hydroxychloroquine ≤14 days.
Has any of the following conditions within the past 6 months: cerebrovascular accident, transient ischemic attack, or another arterial thromboembolic event.
Has uncontrolled or significant cardiovascular disease, including the following:
a. Has a corrected QT interval (by Fridericia’s formula) >470 ms (females) or >450 ms (males) based on average of the Screening triplicate12-lead electrocardiogram (ECG).
b. Diagnosed or suspected long QT syndrome or known family history of long QT syndrome.
c. History of clinically relevant ventricular arrhythmias, such as ventricular tachycardia, ventricular fibrillation, or Torsade de Pointes.
d. Subject has bradycardia of less than 50 bpm unless the subject has a pacemaker.
e. History of second- or third-degree heart block. Subjects with a history of heart block may be eligible if they currently have pacemakers and have no history of fainting or clinically relevant arrhythmia with pacemakers.
f. Acute myocardial infarction within 6 months prior to Screening.
g. Uncontrolled angina pectoris within 6 months prior to Screening.
h. Symptomatic congestive heart failure defined as New York Heart Association Class II to IV.
i. Coronary/peripheral artery bypass graft or any coronary/peripheral angioplasty within 6 months prior to Screening.
j. Grade ≥3 hypertension, graded according to the NCI-CTCAE V5.0.
k. Complete left or right bundle branch block.
l. Left ventricular ejection fraction (LVEF) <50% by either an echocardiogram (ECHO) or a multigated acquisition (MUGA) scan.
Has clinically significant corneal disease.
Has history of (non-infectious) ILD/pneumonitis that required corticosteroids, current ILD/pneumonitis, or suspected ILD/pneumonitis that cannot be ruled out by imaging at Screening.
Has clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses, including, but not limited to, any underlying pulmonary disorder (eg, pulmonary emboli within 3 months of randomization, severe asthma, severe COPD, restrictive lung disease, pleural effusion, etc) and potential pulmonary involvement caused by any autoimmune, connective tissue, or inflammatory disorders (eg, rheumatoid arthritis, Sjögren’s syndrome, sarcoidosis, etc), prior pneumonectomy, or requirement for supplemental oxygen.
On chronic steroid treatment (dose of 10 mg daily or more prednisone equivalent), except for low-dose inhaled steroids (for asthma/COPD), 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, except adequately resected non-melanoma skin cancer, curatively treated in situ disease, superficial gastrointestinal tract tumors, and non-muscle invasive bladder cancer curatively resected by endoscopic surgery.
Has history of allogeneic bone marrow, stem cell, or solid organ transplant.
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. Note: Subjects may be enrolled with chronic, stable Grade 2 toxicities (defined as no worsening to Grade >2 for at least 3 months prior to randomization and managed with SoC treatment) that the investigator deems related to previous anticancer therapy, following discussion with the Sponsor, such as the following:
a. Chemotherapy-induced neuropathy
b. Endocrinopathies, which may include hypothyroidism, hyperthyroidism, type I diabetes, hyperglycemia, adrenal insufficiency, and adrenalitis
c. Skin hypopigmentation (vitiligo)
Has history of hypersensitivity to any study 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. Note: Subjects with localized fungal infections of the skin or nails are eligible.
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. Subjects are eligible if:
a. CD4+ T-cell count ≥350 cells/mm3 at the time of screening
b. Virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) at the time of screening and for at least 12 weeks before screening
c. No AIDS–defining opportunistic infections or conditions within the past 12 months
d. On stable ART regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (Day 1) and agree to continue ART throughout the study.
- Has active or uncontrolled hepatitis B or C infection. Hepatitis B and/or Hepatitis C screening tests are not required unless there is a known history of HBV and/or HCV infection or if mandated by local health authority. Subjects are eligible if:
a. Are HbsAg positive with chronic HBV infection (lasting 6 months or longer) and meet conditions below:
i HBV DNA viral load <2000 IU/mL
ii Start or maintain antiviral treatment if clinically indicated as per the investigator.
b. Have normal transaminase values, or, if liver metastases are present, abnormal transaminases with a result of AST/ALT <3 × ULN, which are not attributable to HBV infection
c. History of hepatitis C infection eligible if the HCV viral load is below the level of detection in the absence of antiviral therapy during the previous 4 weeks.
d. Have normal transaminase values, or, if liver metastases are present, abnormal transaminases with a result of AST/ALT <3 × ULN, which are not attributable to HCV infection
- Has active, known, or suspected autoimmune disease. The following examples may be enrolled as an exception:
a. Type I diabetes mellitus/hypothyroidism only requiring hormone replacement
b. Skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment
c. Conditions not expected to recur in the absence of an external trigger
Has any evidence of severe or uncontrolled systemic diseases (including active bleeding diatheses, psychiatric illness/social situations, substance abuse) or other factors that, in the investigator’s opinion, make it undesirable for the subject to participate in the study or would jeopardize compliance with the protocol. Screening for chronic conditions is not required.
Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live-attenuated vaccines and are not allowed.
Female who is pregnant or breastfeeding or planning to become pregnant.
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 psychological, social, familial, or logistical factors that would prevent regular follow-up.
