Safety, Tolerability, Pharmacokinetics, Biological, and Clinical Activity of AGEN2034 in Subjects With Metastatic or Locally Advanced Solid Tumors, With Expansion to Second-Line Cervical Cancer

Inclusion Criteria:

• Safety Cohort (Dose Escalation)

  1. Signed written informed consent.
  2. Age ≥18 years.
  3. Histologically or cytologically proven metastatic or locally advanced solid tumors for which no standard therapy exists or standard therapy has failed. Availability of tumor archival material or fresh biopsies is optional for subjects in dose escalation.
  4. ECOG performance status of 0 to 1 at trial entry and estimated life expectancy of ≥3 months.
  5. Evidence of objective disease. A measurable lesion is not necessary.
  6. Adequate hematological function defined by white blood cell (WBC) count ≥3 × 10^9/L; absolute neutrophil count (ANC) ≥1.5 × 10^9/L; lymphocyte count ≥0.5 × 10^9/L; platelet count ≥100 × 10^9/L; and hemoglobin ≥9 g/dL (may have been transfused).
  7. Adequate hepatic function, defined as total bilirubin ≤1.5 × upper limit of normal (ULN); AST ≤2.5 × ULN; and ALT ≤2.5 × ULN. For subjects with documented metastatic disease to the liver, AST and ALT: ≤5 × ULN.
  8. Adequate renal function, defined as estimated creatinine clearance >50 mL/min according to Cockcroft-Gault formula or measured 24-hour creatinine clearance (or local institutional standard method).
  9. Effective contraception for both male and female subjects if risk of conception exists.

• Efficacy Expansion Cohort (Second-Line Cervical Cancer)

  1. Signed written informed consent.
  2. Age ≥18 years.

  3. Subjects must have recurrent, unresectable, or metastatic cervical cancer and have relapsed after a platinum-containing doublet administered for treatment of advanced (recurrent, unresectable, or metastatic) disease.

     Subjects must have persistent, recurrent, or metastatic squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma of the cervix, with documented disease progression (disease not amenable to curative therapy).

     Note: The following cervical tumors are not eligible: minimal deviation/adenoma malignum, gastric type adenocarcinoma, clear cell carcinoma and mesonephric carcinoma. Histologic confirmation of the original primary tumor is required via pathology report.

     Subjects must have had one prior systemic chemotherapeutic regimen for management of persistent, recurrent, or metastatic carcinoma of the cervix (e.g., paclitaxel/cisplatin, paclitaxel/cisplatin/bevacizumab). Chemotherapy administered concurrently with primary radiation (e.g., weekly cisplatin) is not counted as a systemic chemotherapy regimen. Adjuvant chemotherapy given following completion of radiation therapy (or concurrent chemotherapy and radiation therapy) is not counted as a systemic chemotherapy regimen (e.g., paclitaxel and carboplatin for ≤4 cycles).

     Note: Subjects who have received >1 prior regimen are not eligible.

  4. ECOG performance status of 0 to 1 at trial entry and estimated life expectancy of ≥3 months.
  5. Availability of a formalin-fixed paraffin-embedded block containing tumor tissue or 7 unstained tumor slides suitable for PD-L1 expression assessment.
  6. Availability of tissue for HPV testing (paraffin block or one 7-µm section on a slide).
  7. Disease must be measurable, with ≥1 unidimensional measurable lesion per RECIST 1.1.
  8. Adequate hematological function, defined as WBC ≥3 × 10^9/L; ANC ≥1.5 × 10^9/L; lymphocyte count ≥0.5 × 10^9/L; platelet count ≥100 × 10^9/L; and hemoglobin ≥9 g/dL (may have been transfused).
  9. Adequate hepatic function, defined as total bilirubin ≤1.5 × ULN; AST ≤2.5 × ULN; and ALT ≤2.5 × ULN.
  10. Adequate renal function, defined as estimated creatinine clearance >30 mL/min according to Cockcroft-Gault formula or measured 24-hour creatinine clearance (or local institutional standard method).
  11. Effective contraception for female subjects if risk of conception exists. Note: Effects of the study drug on the developing human fetus are unknown. Thus, women of childbearing potential and men must agree to use effective contraception, defined as 2 barrier methods, or 1 barrier method with a spermicide, an intrauterine device or use of oral female contraceptive. Effective contraception must be used 30 days before first study drug administration, for the duration of trial participation, and ≥60 days after stopping trial participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this trial, the treating physician should be informed immediately.

Exclusion Criteria:

• Safety and Expansion Cohorts

  1. Concurrent treatment with a non-permitted drug.
  2. Prior therapy with any antibody/drug targeting T-cell co-regulatory proteins (immune checkpoints) such as anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibodies. For subjects with metastatic melanoma, prior treatment with CTLA-4-blocking antibody is permissible.

  3. Concurrent anticancer treatment (e.g., cytoreductive therapy, radiotherapy except for palliative bone-directed radiotherapy, immune therapy, or cytokine therapy except for erythropoietin) within 28 days before start of trial treatment; major surgery within 28 days before start of trial treatment (excluding prior diagnostic biopsy); use of hormonal agents within 7 days before start of trial treatment, except for subjects with castration-resistant prostate cancer (CRPC), who may remain on treatment with luteinizing hormone-releasing hormone agonists or antagonists; or use of any investigational drug within 28 days before start of trial treatment.

     Note: Small molecule or antibody targeted therapy is permissible <14 days from start of trial treatment.

  4. Subjects receiving immunosuppressive agents (such as steroids) for any reason should be tapered off these drugs 14 days before initiation of study treatment. Steroids with no or minimal systemic effect (topical, inhalation) are allowed.

     Note: Subjects receiving bisphosphonate or denosumab are eligible provided that treatment was initiated ≥14 days before first dose of AGEN2034.

     Note: Use of inhaled or topical corticosteroid is permitted. Note: Steroid pre-medication for radiographic imaging for dye allergies is permitted.

  5. Previous malignant disease (other than target malignancy to be investigated in this trial) within the last 5 years, with the exception of basal or squamous cell carcinoma of the skin.
  6. Rapidly progressive disease.
  7. Active or history of central nervous system metastases.
  8. Receipt of any organ transplantation, including allogeneic stem-cell transplantation.

  9. Significant acute or chronic infections, including:

     • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
     • Positive test for hepatitis B virus (HBV) surface antigen and/or confirmatory hepatitis C virus (HCV) RNA (if anti-HCV antibody tested positive).
  10. Active or history of any autoimmune disease (subjects with diabetes type 1, vitiligo, psoriasis, hypo-, or hyperthyroid disease not requiring immunosuppressive treatment are eligible) or immunodeficiencies.
  11. Known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE grade ≥3), any history of anaphylaxis, or uncontrolled asthma (i.e., ≥3 features of partly controlled asthma).
  12. Persisting toxicity related to prior therapy of NCI CTCAE grade >1 severity. Sensory neuropathy of grade ≤2 is acceptable.
  13. Pregnancy or breast feeding.
  14. Known alcohol or drug abuse.
  15. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (<6 months before enrollment), myocardial infarction (<6 months before enrollment), unstable angina, congestive heart failure (New York Heart Association class ≥II), or serious uncontrolled cardiac arrhythmia requiring medication.
  16. All other significant diseases (e.g., inflammatory bowel disease) that, in the opinion of the investigator, might impair the subject's tolerance of trial treatment.
  17. Any psychiatric condition that would prohibit understanding or rendering of informed consent.
  18. Legal incapacity or limited legal capacity.
  19. Vaccination within 4 weeks of first dose of AGEN2034 and while on study except for administration of inactivated vaccines (e.g., inactivated influenza vaccines).