NPX372, a B7-H7:CD3 Bispecific Antibody, in Selected Solid Tumor Malignancies

A Phase 1 Dose-Escalation Study of NPX372, a Bispecific Antibody Targeting B7-H7 and CD3, in Selected Solid Tumor Malignancies

NPX372 is an antibody drug (protein drug) that blocks a specific protein which is found to be increased on the surface of cancer cells called B7-H7 and, at the same time, binds to immune cells (T cells) through a receptor called CD3. The effect of this binding is to activate T cells to kill cancer cells with B7-H7.

In this research study we are:

• Evaluating the safety and possible effectiveness of NPX372.
• Identifying a safe and tolerable dose or doses for further study.

Participants who are treated will receive an intravenous (IV) infusion of NPX372 if their disease has not progressed, and be closely monitored by the treating physicians.

NPX372 is being developed as a therapeutic in solid tumor malignancies including non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma (CRC), pancreatic adenocarcinoma (PDAC), biliary tract tumors, ovarian carcinoma, and gastric/gastro-esophageal carcinoma. This study is a Phase 1 study with primary dose-escalation occurring in the aforementioned solid tumor malignancies (main cohorts). Backfill cohorts from a selected subset of these tumor types will be utilized to enrich for dose optimization in participants whose tumors have high B7-H7 expression determined by prospective screening of archival tissue.

INCLUSION CRITERIA:

• Ability to understand and the willingness to sign a written informed consent document.

• Histologically or cytologically confirmed recurrent or metastatic solid tumor refractory to standard of care therapy in one of the following indications: NSCLC, RCC, CRC, PDAC, biliary tract tumors, gastric and gastro-esophageal carcinoma, and ovarian carcinoma.

• Measurable disease by RECIST v1.1 criteria.

• Age ≥19 years.

• Adequate organ function as defined by:

  • Calculated creatinine clearance (CrCl) must be ≥45 mL/min (by Cockroft-Gault formula).
  • Total bilirubin ≤1.5× the upper limit of normal (ULN) unless prior history of Gilbert's syndrome who must have total bilirubin <3.0 mg/dL.
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5× ULN, or ≤5× ULN if due to liver involvement by tumor.
  • Serum albumin ≥3.0 g/dL.
  • Hemoglobin ≥9.0 g/dL, limited transfusion to reach this value may be allowed after discussion with the Sponsor's Medical Monitor.
  • Platelets ≥100 × 109 cells/L.
  • Absolute neutrophil count ≥1.5 ×109 cells/L.
  • Baseline oxygen saturation > 90% on room air

• All participants will be required to have sufficient archival tissue available. For backfill cohort participants, archival tissue will be used to confirm B7-H7 expression for enrollment (see inclusion criterion 2) during pre-screening.

  -If 3 participants are already enrolled in any backfill cohort, subsequent participants will be required to have a fresh biopsy during the screening period. These participants should therefore only be selected if judged safe to undergo a fresh biopsy.

• Male participants with a female partner(s) of childbearing potential must agree to use highly effective contraceptive measures throughout the trial starting with the Screening visit through 60 days after the last dose of study drug is received. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.

EXCLUSION CRITERIA:

• Prior treatment toxicity not resolved to grade 1 or below including any:

  • Systemic anti-cancer treatment: exceptions include alopecia, chronic stable neuropathy for >4 months, change in skin pigmentation, grade 2 anemia, or requiring replacement therapy for endocrine abnormalities (in this setting, symptoms should have resolved to grade 1 or below). Systemic anti-cancer treatment within 10 days prior to start of study is not allowed.
  • Limited-field radiotherapy: radiation therapy within 7 days prior to start of study or extended-field thoracic radiotherapy within 8 weeks of the first dose of study drug is not allowed.
  • Major surgery: major surgery (excluding placement of catheters, vascular access, or biopsy) within 4 weeks of the first dose of study drug is not allowed.

• Clinically or radiographically unstable brain metastases: Participants with known brain metastases should be clinically stable and asymptomatic. Participants with a history of brain metastases should have an MRI during screening. For participants who are noted to have new or enlarging brain metastases during screening, treatment with stereotactic radiosurgery (SRS) is permitted with the standard limited field radiotherapy washout of >7 days. Participants requiring more extensive radiation (ie, fractionated stereotactic radiation or whole-brain radiation) would need a washout period of ≥4 weeks. Participants should be off corticosteroids for central nervous system (CNS) treatment for at least 7 days prior to dosing.

• Cardiac conditions as follows: history of congestive heart failure (CHF) Class III/IV according to the New York Heart Association (NYHA) Functional Classification; cardiac arrhythmias >Grade 2, unstable angina, coronary/peripheral artery bypass graft within 3 months, or evidence of 2nd- or 3rd-degree heart block.

• Uncontrolled intercurrent illness including, but not limited to, uncompensated respiratory, cardiac, hepatic, or renal disease, active infection (including hepatitis B virus [HBV], hepatitis C virus [HCV], human immunodeficiency virus [HIV] infections except as below, and active clinical tuberculosis), or renal transplant; ongoing or active infection, or social situations that would limit compliance with study requirements.

  • HIV: Seropositive participants without an acquired immunodeficiency syndrome (AIDS) defining illness and those with AIDS defining conditions on anti-retroviral therapy (ART) are eligible if they are healthy and have a CD4 count >350 cells/mm3 at the time of screening (Day ≤28 days). Participants on ART must have HIV RNA levels <50 copies/mL or the lower limit of quantification (LLOQ) using a local assay at the time of screening. Participants on ART must have been on a stable regimen without dose modification for at least 4 weeks prior screening.
  • HBV: Participants with HBsAg positivity are eligible if they have undetectable viral load and have received HBV anti-viral therapy for at least 4 weeks prior to screening.
  • HCV: Participants with a history of HCV infection are eligible if they have undetectable HCV viralload at screening and have completed curative therapy >4 weeks prior to screening.

• Any evidence of hemoptysis or gastrointestinal (GI) bleeding within the last 3 months prior to screening.

• Known autoimmune disease requiring immunosuppressive treatment requiring the equivalent of more than 10 mg prednisone daily.

• History of unresolved prior immune-related toxicity except for endocrine abnormalities requiring replacement therapy or vitiligo.

• Prior treatment with a cytokine therapy or cytokine fusion therapy.

• History of prior or concomitant malignancy that requires other active treatment except for prostate cancer without radiographic evidence of disease on long-term androgen deprivation therapy for >6 months (ie, leuprolide).