IRB Study Number 25-170
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
1) To evaluate the safety and tolerability of LNCB74
2) To determine the maximum tolerated dose (MTD), maximum administered dose (MAD) and/or recommended Phase 2 doses (RP2D) of LNCB74
Secondary Objectives
1) To characterize the PK profile of total ADC (TADC), total antibody (TAb),, and unconjugated MMAE from LNCB74
2) To characterize the immunogenicity of LNCB74
3) To assess the preliminary anti-tumor activity of LNCB74 per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by Investigator
4) To correlate baseline B7-H4 expression with anti-tumor activity of LNCB74
Inclusion Criteria
1) The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
2) Be ≥ 18 years of age on day of signing informed consent.
3) Participant with histologically or cytologically confirmed diagnosis of the following advanced unresectable and/or metastatic solid tumors who have progressed on, are not a candidate for, or are intolerant of existing therapy(ies) known to provide clinical benefit:
a. Part 1 (Dose Escalation, Safety Backfill, Biomarker Backfill):
i) The following tumor types may be enrolled:
• Platinum-resistant high-grade serous, high-grade endometrioid, or clear cell ovarian cancer, fallopian tube cancer, primary peritoneal cancer
• Treatment refractory breast cancer of the following subtypes: triple negative breast cancer (TNBC), HER2 overexpression (IHC3+ or in-situ hybridization (ISH*)+) or HER2-low expression (IHC2+/ISH*-, IHC1+/ISH*-, or IHC1+/ISH* untested), and hormone receptor (HR) positive/HER2 negative or low breast cancer
• endometrial cancer
• biliary tract cancer (BTC)
• non-small cell lung cancer (NSCLC), squamous cell type
*ISH: fluorescence in situ hybridization (FISH) or dual color in situ hybridization (DISH)
ii) For Participants in Safety Backfill or Biomarker Backfill: Participants have documented B7-H4 expression by IHC 1+/2+/3+ staining in at least ≥ 1% (Safety Backfill) or ≥50% (Biomarker Backfill) of tumor cells as confirmed by CLIA-certified central lab and validated B7-H4 assay on tumor tissue obtained from an archival biopsy ≤5 years of pre-screening or a fresh biopsy if archival tissue is not available.
b. Part 2 (Dose Expansion/Optimization):
i) The following tumor types may be enrolled:
• platinum-resistant high grade serous, high-grade endometrioid, or clear cell ovarian cancer, fallopian tube cancer, primary peritoneal cancer
• treatment-refractory breast cancer of the following subtypes: triple-negative breast cancer (TNBC), HER2 overexpression (IHC3+ or in-situ hybridization (ISH*)+) or HER2-low expression (IHC2+/ISH*-, IHC1+/ISH*-, or IHC1+/ISH* untested), and hormone receptor (HR) positive/HER2 negative or low breast cancer
ii) Participants have documented B7-H4 expression by IHC 1+/2+/3+ staining in at least 10% of tumor cells as confirmed by CLIA-certified central lab and validated B7-H4 assay on tumor tissue obtained from an archival biopsy ≤5 years of pre-screening or a fresh biopsy if archival tissue is not available.
Note: Participants must have had disease progression after at least one line of systemic standard-of-care therapy prior to enrollment. Participants who discontinue standard treatment due to intolerance will also be eligible to enroll.
Additional Notes for Ovarian, Fallopian tube, or Primary Peritoneal Cancer:
• Platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer is defined as recurrence within 6 months of last platinum dose as determined by the investigator.
• For participants with platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer, prior treatment must have included at least 1 and up to 5 prior lines of treatment, including at least 1 platinum-based regimen. Participants harboring a BRCA1 or 2 mutations should have received a PARP inhibitor.
Additional Notes for Breast Cancer:
• For participants with HER2-negative/low breast cancer (defined at IHC0 or 1+, or IHC2+ and ISH-non-amplified), treatment must have included at least 1 and up to 3 prior chemotherapy regimens for metastatic disease, plus up to 2 prior antibody drug conjugate regimens (e.g., sacituzumab govitecan, trastuzumab deruxtecan).
• For participants with HER2-negative/low breast cancer that is ER-positive (>1% ER-positive by IHC), systemic treatment must have also included: (1) at least 1 prior line of endocrine therapy plus a CDK4/6 inhibitor, and (2) a PIK3CA inhibitor if known to have a somatic PIK3CA activating mutation (by tumor or ctDNA assay) sensitive to the PIK3CA inhibitor alpelisib or another FDA-approved PI3KA or AKT inhibitor (eg, capivasertib).
• For participants with HER2-positive breast cancer (defined at 3+ IHC positive and/or ISH-amplified), systemic treatment must have included at least 1 prior regimen including chemotherapy plus an anti-HER2-antibody (trastuzumab or pertuzumab), and at least 1 anti-HER2 ADC (trastuzumab deruxtecan, and/or trastuzumab emtansine).
Additional Notes for Endometrial cancer:
• Participants with endometrial cancer must have received, be ineligible for, or intolerant of a platinum doublet standard of care chemotherapy with/without anti-PD(L1)-1 treatment
Additional Notes for NSCLC, squamous cell type:
• Participants with NSCLC, squamous must have received, be ineligible for, or intolerant of a platinum doublet standard of care chemotherapy and prior anti-PD(L1)-1 treatment
Additional Notes for Biliary Tract Cancer:
• Participants with biliary tract cancer must have received, be ineligible for, or intolerant of a platinum doublet standard of care chemotherapy with/without anti-PD(L1)-1 treatment
4) A male participant must agree to use contraception and refrain from sperm donation or expecting to father a child, from Screening through the treatment period and for at least 90 days after the last dose of study treatment.
5) A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
a. Not a woman of childbearing potential (WOCBP)
b. A WOCBP who agrees to follow contraceptive guidance outlined in from Screening through the treatment period and for at least 90 days after the last dose of study treatment.
6) Have measurable disease per RECIST 1.1 as assessed by the local site investigator/radiology. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.
7) Able to provide tumor tissue sample (archival or newly obtained core or excisional biopsy) at Screening (Part 1) or Pre-screening (Part 2) of a tumor lesion not previously irradiated for retrospective (Part 1) or prospective (Part 2) B7-H4 testing. Note: Archival tissue should be obtained within 5 years of the date of informed consent.
8) For Part 1B Biomarker Backfill Cohorts and Part 2: Willing to undergo fresh tumor biopsy at Screening and On-treatment (6 weeks +/-1 weeks) from a lesion that can be biopsied at an acceptable clinical risk as judged by the investigator. Note: If archival tissue is available from a prior biopsy performed ≤6 months of enrollment, the fresh biopsy at Screening may be waived.
9) Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
10) Life expectancy greater than or equal to 12 weeks as judged by the Investigator.
11) Have adequate organ function as defined in the following table (Table 2). Specimens must be collected within 10 days before starting study treatment.
Exclusion Criteria
1) A WOCBP who has a positive serum pregnancy test (within 72 hours) prior to treatment.
2) Has received prior investigational agents within 4 weeks (could consider shorter interval for kinase inhibitors or other short half-life drugs) prior to treatment.
Note: Participants must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline. Participants with endocrine-related AEs Grade ≤ 2 requiring treatment or hormone replacement may be eligible.
3) Has received anti-cancer chemotherapy (Immunotherapy (non-antibody-based therapy), retinoid therapy, hormonal therapy within 2 weeks prior to treatment.
4) Has received antibody-based anti-cancer therapy within 4 weeks prior to treatment.
5) Has received targeted agents and small molecules (such as 5-fluorouracil-based agents, folinic agents, weekly paclitaxel, small molecule tyrosine kinase inhibitors) within 2 weeks or 5 half-lives, whichever is longer.
6) Has received prior platinum-based chemotherapy and progressed within 4 weeks of initiating therapy (platinum-refractory disease)
7) Has received an ADC with MMAE payload.
8) Has received prior radiotherapy within 2 weeks of start of study treatment for focal radiation or within 4 weeks for wide-field radiotherapy (eg, >30% of marrow-bearing bones).
Note: Participants must have recovered from all radiation-related toxicities and do not require corticosteroids. A 1-week washout is permitted for palliative focal radiation (≤ 2 weeks of radiotherapy) to non-CNS disease.
9) Has received G-CSF or GM-CSF within 7 days prior to start of study treatment.
10) Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention.
Note: Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox/zoster, 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 (e.g., FluMist®) are live attenuated vaccines and are not allowed.
11) Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
12) Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of bladder, which have undergone potentially curative therapy are not excluded.
13) Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment.
14) Has severe hypersensitivity (≥ Grade 3), known allergy or reaction LNCB74 or any of its excipients.
15) Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.
16) Has active ≥Grade 2 sensory or motor neuropathy.
17) Has active or chronic corneal disorders, other active ocular conditions requiring ongoing therapy or any clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy.
18) Has an active infection requiring systemic therapy.
19) Any major surgery within 4 weeks of study drug administration. Participants must have recovered from the effects of major surgery or significant traumatic injury at least 14 days before the first dose of study treatment.
Note: Participant must have recovered adequately from the procedure and/or any complications from the surgery prior to starting study intervention.
20) Toxicity (except for alopecia) related to prior anti-cancer therapy and/or surgery, unless the toxicity is either resolved, returned to baseline or Grade 1, or deemed irreversible.
21) Prior organ or tissue allograft.
22) Uncontrolled or significant cardiovascular disease including, but not limited to any of the following:
i. Myocardial infarction or stroke/transient ischemic attack within the past 6 months
ii. Uncontrolled angina within the past 3 months;
iii. Any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or torsades de pointes);
iv. History of other clinically significant heart disease (e.g., cardiomyopathy, congestive heart failure with New York Heart Association functional classification III to IV pericarditis or significant pericardial effusion);
v. Cardiovascular disease-related requirement for daily supplemental oxygen therapy;
vi. QT interval corrected for heart rate using Fridericia’s formula (QTcF) prolongation > 470 msec, except for right bundle branch block;
23) Participants with serious or uncontrolled medical disorders.
24) Participants who are on total parenteral nutrition (TPN)
25) Participants with history of bowel obstruction within one month of screening
26) Participants with history of significant ascites requiring paracentesis within 2 weeks of screening
27) Has a known history of human immunodeficiency virus (HIV) infection with an acquired immune deficiency syndrome (AIDS)-defining opportunistic infection within the last year, or a current CD4 count <350 cells/μl. Note: No HIV testing is required unless mandated by local health authority.
28) Has known active Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection. Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
29) Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating Investigator.
30) Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
