IRB Study Number 24-211
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
● To compare the OS between the experimental (sigvotatug vedotin) and control (docetaxel) arms
● To compare the ORR as assessed by blinded independent central review (BICR) between the experimental and control arms
Secondary Objectives
● To compare PFS as assessed by BICR between the experimental and control arms
Inclusion Criteria
Age ≥18 years and legally an adult at time of consent, and ≥ the age of majority per regional requirements.
Histologically or cytologically confirmed diagnosis of locally advanced, unresectable (Stage IIIB, IIIC), or metastatic (Stage IV: M1a, M1b, or M1c) NSCLC per the American Joint Committee on Cancer (AJCC) Staging Manual, Version 8.0, and the Union for International Cancer Control (UICC) Staging System (Eighth edition).
Participants must have NSCLC with nonsquamous histology:
Tumors with squamous, or predominantly squamous histology are excluded.
Tumors with small cell elements are excluded.
Participants who have NSCLC with known AGAs are permitted (eg, EGFR mutations, ALK translocations).
Participants must have received the following prior therapies and progressed during or relapsed after receiving their most recent prior therapy:
Participants with no known AGAs must fulfill 1 of the following conditions:
o Received a platinum-based combination therapy for the treatment of metastatic or recurrent disease and a PD-(L)1 monoclonal antibody (concurrently or sequentially with platinum-based chemotherapy), unless contraindicated.
o Experienced disease progression within 6 months of the last dose of platinum-based chemotherapy in the adjuvant, neoadjuvant, or chemoradiotherapy setting and received a PD-(L)1 monoclonal antibody at any time during the course of treatment.
Participants with known AGAs (eg, EGFR mutations, ALK translocations, or other relevant actionable mutations) must fulfill the following conditions:
o Must have received at least 1 relevant AGA-targeted therapy and, in the opinion of the investigator, additional AGA-targeted therapy is not in the best interest of the participant.
o Received a platinum-based combination therapy for the treatment of metastatic or recurrent disease, or experienced disease progression within 6 months of the last dose of platinum-based chemotherapy in the adjuvant, neoadjuvant, or chemoradiotherapy setting.
o May have received up to 1 PD-(L)1 monoclonal antibody (concurrently or sequentially with platinum-based chemotherapy).
Measurable disease based on RECIST v1.1, as determined by investigator.
An ECOG performance status score of 0 or 1. Refer to https://ecog-acrin.org/resources/ecog-performance-status for the most recent version of ECOG.
Adequate organ function as defined by the following baseline laboratory criteria obtained within 7 days prior to study intervention initiation (Cycle 1 Day 1):
Participants of childbearing potential (as defined in Section 10.4) under the following conditions:
Must have a negative serum pregnancy test (beta human chorionic gonadotropin [βhCG] with minimum sensitivity 25 mIU/mL or equivalent quantitative assay) result within 72 hours prior to Cycle 1 Day 1. Participants with false positive results and documented verification that the participant is not pregnant are eligible for participation.
Must agree not to become pregnant during the study and for at least 2 months after the final dose of study intervention.
Must agree not to breastfeed or donate ova, from the time of informed consent and continuing through at least 2 months after the final dose of study intervention.
If sexually active in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of birth control (contraception), at least 1 of which must be highly effective (as defined in Section 10.4) from the time of informed consent and continuing through at least 2 months after the final dose of study intervention.
- Participants who can get someone pregnant (as defined in Section 10.4) under the following conditions:
Must agree not to donate sperm from the time of informed consent and continuing through at least 4 months after the final dose of study intervention.
If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use at least 2 acceptable methods of birth control (contraception), at least 1 of which must be highly effective (as defined in Section 10.4) from the time of informed consent and continuing through at least 4 months after the final dose of study intervention.
If sexually active with a person who is pregnant or breastfeeding, must consistently use a condom (as defined in Section 10.4) from the time of informed consent and continuing through at least 4 months after the final dose of study intervention.
- Able to provide any of the following tumor tissues for biomarker analysis:
Archival specimen (preferably collected within 2 years of consent) (see laboratory manual for details); or
Fresh tissue from a tumor lesion, if medically feasible.
Enrollment of participants who cannot provide archival or fresh tumor tissue per the above requirements must be discussed with the sponsor’s medical monitor.
- The participant or the participant’s legally authorized representative must provide documented informed consent.
Exclusion Criteria
Life expectancy of <3 months in the opinion of the investigator.
Known allergies/hypersensitivity/intolerance to or contraindication of taxanes, docetaxel, or any excipient contained in the drug formulation of sigvotatug vedotin.
Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association Class III-IV within 6 months prior to Cycle 1 Day 1.
History of another malignancy within 3 years before Cycle 1 Day 1, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (eg, 5-year OS ≥90%), such as adequately treated carcinoma in situ of the cervix, nonmelanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
Participants with any of the following respiratory conditions:
Evidence of noninfectious ILD or pneumonitis that:
o Was previously diagnosed and required systemic steroids, or
o Is currently diagnosed and managed, or
o Is suspected on radiologic imaging at screening
Known DLCO (adjusted for hemoglobin) <50% predicted
Any Grade ≥3 pulmonary disease unrelated to underlying malignancy including, but not limited to:
o Pulmonary emboli within 3 months of Cycle 1 Day 1
o Severe asthma requiring systemic corticosteroids within 30 days prior to Cycle 1 Day 1 or is not well controlled with low-dose inhaled corticosteroids/long-acting beta-2 agonists
o Severe chronic obstructive pulmonary disease requiring supplemental oxygen or systemic corticosteroids
o Any autoimmune or inflammatory disorders with significant pulmonary parenchymal involvement at time of screening (ie, rheumatoid arthritis, Sjögren's syndrome, sarcoidosis, etc)
Major surgery (defined as a surgery requiring inpatient hospitalization of at least 48 hours) within 21 days or minor surgery within 7 days prior to Cycle 1 Day 1. Participants must have recovered adequately from the toxicity or complications from the surgery prior to starting study intervention. Participants who are planning a major surgery during the treatment period must be excluded from the study.
Receipt of a live vaccine within 30 days prior to Cycle 1 Day 1.
Pre-existing peripheral neuropathy Grade ≥2 per NCI CTCAE v5.0.
Uncontrolled diabetes mellitus, defined as HbA1c ≥8.0% or HbA1c between 7% and <8.0% with associated diabetes symptoms (polyuria or polydipsia) that are not otherwise explained.
Prior therapy:
Prior treatment with antimicrotubule agents (taxanes, vinca alkaloids, or MMAEs) in the locally advanced, unresectable/refractory, or metastatic setting.
Prior antimicrotubule agent exposure in curative settings (including adjuvant, neoadjuvant, or chemoradiotherapy) is permissible.
Received more than 1 prior line of cytotoxic chemotherapy in the locally advanced, unresectable/refractory, or metastatic setting.
Prior cytotoxic chemotherapy in curative settings is permissible.
At least 14 days must have elapsed from the last dose of radiotherapy until Cycle 1 Day 1. Participants must have recovered from all radiation-related toxicities that would otherwise prevent trial participation. Palliative radiotherapy within the 14 days prior to Cycle 1 Day 1 may be allowed upon discussion with the sponsor’s medical monitor or their designee.
Prior radiation therapy to the lung parenchyma that is >30 Gray (Gy) within 6 months of Cycle 1 Day 1.
Any systemic anticancer therapy (standard or experimental) within 21 days prior to Cycle 1 Day 1.
Participants with Grade ≥2 ongoing toxicities associated with prior therapies will be excluded, with the exception of alopecia.
- History of or a currently ongoing infection, including:
Currently receiving systemic antimicrobial treatment for active infection (viral, bacterial, or fungal) at the time of randomization. Routine antimicrobial prophylaxis is permitted.
Known seropositivity of human immunodeficiency virus (HIV), except for participants with controlled HIV infection on a stable regimen of antiretroviral therapy (ART). The investigator should ensure the ART does not result in substantial interactions with study or concomitant medications.
Positive for hepatitis B by surface antigen expression.
Active hepatitis C infection (positive by polymerase chain reaction [PCR]). Participants who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response 12 weeks after completion of antiviral therapy.
Note: Testing for HIV or hepatitis B and C is required when mandated by local health authorities.
- Ongoing immune-mediated AEs related to prior treatment with PD-L(1) inhibitors Participants with adequately controlled and stable Grade ≤2 endocrinopathies may be enrolled.
Participants with active Grade ≥3 immunotherapy-related endocrinopathies are excluded.
Participants with ongoing immunotherapy-related myocarditis, colitis, or uveitis are excluded.
Participants with other immunotherapy-related AEs requiring high doses of steroids (>20 mg/day of prednisone or equivalent) are excluded.
- Active central nervous system (CNS) lesions, including leptomeningeal metastasis, are excluded. Participants with definitively treated brain metastases (surgery and/or radiotherapy) are eligible if they meet the following criteria:
CNS metastases have been clinically stable for at least 4 weeks prior to treatment initiation and baseline scans show no evidence of new or enlarged metastasis.
The participant is on a stable dose of ≤10 mg/day of prednisone or equivalent for at least 2 weeks (if requiring steroid treatment).
Treatment with corticosteroids occurring >1 month prior to the Screening visit unless it is allowed as a concomitant therapy as specified in Section 6.8.2. Anticonvulsants at a stable dose are allowed.
No evidence of clinical and radiographic disease progression in the CNS for ≥21 days after definitive radiotherapy and/or surgery.
Current therapy with other investigational agents.
Other serious underlying medical condition that, in the opinion of the investigator, would impair the participant’s ability to receive or tolerate the planned treatment and follow-up.
Investigator site staff directly involved in the conduct of the study and their family members, site staff otherwise supervised by the investigator, and sponsor and sponsor delegate employees directly involved in the conduct of the study and their family members.
