Ensayos clínicos

Inclusion Criteria:

• Adult, age 18 years or older, willing and able to provide written informed consent.
• Histologically confirmed advanced malignancy, defined as:
  • Part A: SC-004 Monotherapy Dose Escalation and SC-004 and ABBV-181 in Combination Dose Escalation may include any of the following tumors for which no further standard or curative therapy exists or is considered appropriate by the Investigator:
    • Epithelial ovarian cancer, including fallopian tube cancer and primary peritoneal cancer, of high-grade serous histology, with platinum refractory or resistant disease after prior treatment with at least 1 platinum based chemotherapeutic regimen;
    • Metastatic or advanced high-grade serous endometrial carcinoma previously treated with at least 1 platinum based chemotherapeutic regimen.
  • Part B: SC-004 Monotherapy and SC-004 and ABBV-181 in Combination Expansion Cohorts will include separate treatment cohort(s) of subjects with the following tumors for which no further standard or curative therapy exists or is considered appropriate by the Investigator:
    • Epithelial ovarian cancer, including fallopian tube cancer and primary peritoneal cancer, of high-grade serous histology, with platinum refractory or resistant disease after prior treatment with at least 1 platinum based chemotherapeutic regimen who have received no more than 5 lines of systemic cytotoxic chemotherapy in the setting of metastatic disease;
    • Metastatic or advanced high-grade serous endometrial carcinoma previously treated with at least 1 platinum based chemotherapeutic regimen.
  • Part B: SC-004 Monotherapy and SC-004 and ABBV-181 in Combination Tissue Collection Substudy will include a cohort(s) of subjects with the following tumors for which no further standard or curative therapy exists or is considered appropriate by the Investigator:
    • Epithelial ovarian cancer, including fallopian tube cancer and primary peritoneal cancer, of high-grade serous histology, with platinum refractory or resistant disease after prior treatment with at least 1 platinum based chemotherapeutic regimen.
• Measurable disease, defined as at least 1 tumor lesion ≥10 mm in the longest diameter or a lymph node ≥15 mm in short-axis measurement assessed by computerized tomography (CT) scan (Response Evaluation Criteria in Solid Tumors [RECIST] v1.1). For dose levels at which single-subject cohorts are planned, measurable disease is not required.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• Minimum life expectancy of at least 12 weeks.
• Availability of an archived or fresh tumor tissue, or a formalin fixed paraffin embedded (FFPE) block with enough tissue left to cut at least twenty slides with 4μm thickness, or at least twenty cut FFPE slides with 4μm thickness, representative of the qualifying malignancy and suitable for IHC testing. For dose levels at which single-subject cohorts are planned, provision of tumor tissue, FFPE block, or FFPE slides is not required.
  • Part A (SC-004 and ABBV-181 combination dose escalation cohorts only); and
  • Part B: Tissue must be submitted and test positive for CLDN6 expression prior to the start of study treatment.
    • Note: The 28-day screening window is not applicable for CLDN6 testing. After obtaining prescreening consent, the tissue sample can be submitted for testing at any time. This may occur prior to signing the main written informed consent.
• Subjects with a history of central nervous system (CNS) metastases must have documentation of stable or improved brain imaging for at least 2 weeks after completion of definitive treatment and within 2 weeks prior to first dose of study drug, while off corticosteroids. Definitive treatment may include surgical resection, whole brain irradiation, and/or stereotactic radiation therapy.
• Recovery to Grade 1 of any clinically significant toxicity (excluding alopecia) prior to initiation of study drug administration.
• Satisfactory laboratory parameters:
  • Absolute neutrophil count (ANC) ≥ 1500/L;
  • Platelet count ≥100,000/L;
  • Hemoglobin ≥.0 g/dL;
  • Serum total bilirubin ≤.5× ULN or ≤× ULN for subjects with Gilbert’s disease;
  • ALT and AST ≤× ULN (≤× ULN if evidence of hepatic involvement by malignant disease);
  • Serum creatinine ≤.5× ULN or estimated glomerular filtration rate (eGFR, Modification of Diet in Renal Disease [MDRD] formula) ≥0 mL/min/1.73m2;
  • Albumin ≥ g/dL;
  • Amylase and lipase ≤.5× ULN (≤× ULN if amylase or lipase is isolated with neither clinical nor radiographic signs of pancreatitis).
• Last dose of any prior therapy administered before the first dose of study drug:
  • Chemotherapy, small molecule inhibitors, radiation, and/or other investigational anticancer agents (excluding investigational monoclonal antibodies): within 2 weeks.
• Prior therapy with any agents targeting immune co-inhibitory receptors (eg, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-cytotoxic T lymphocyte-associated antigen 4 [CTLA-4]), or costimulatory receptor activators, monoclonal antibodies, ADCs, radio-immunoconjugates, or T-cell or other cell based therapies: within 4 weeks (2 weeks permissible if unequivocal PD is documented).
• Subject must be either postmenopausal defined as:
  • Age >55 years with no menses for 12 or more months without an alternative medical cause;
  • Age ≤5 years with no menses for 12 or more months without an alternative medical cause and a follicle stimulating hormone (FSH) level >40 IU/L;
  • or
  • Permanently surgical sterile (bilateral oophorectomy, bilateral salpingectomy, or hysterectomy);
  • or
  • A woman of childbearing potential (WOCBP) practicing at least one protocol-specified method of birth control (Section 4.3.1) starting at Study Day 1 through at least 6 months after the last dose of study drug.
• Females of childbearing potential must have a negative serum pregnancy test result at Screening and a predose negative urine pregnancy test on Cycle 1 Day 1 (C1D1). Females of nonchildbearing potential (either postmenopausal or permanently surgically sterile as defined in Section 4.3) at Screening do not require pregnancy testing.

Additional Inclusion Criteria for the Tissue Collection Substudy

• Provide informed consent to participate in the tissue collection substudy.
• Must have at least 2 measurable target lesions per RECIST v1.1.
• Subject must have at least one tumor lesion, including lymph node, that is accessible for pretreatment fresh tumor biopsy:
  • The node or lesion must be deemed accessible for biopsy;
  • The node or lesion must be >1.5 cm in shortest diameter;
  • The node or lesion for biopsy must not be a target lesion used for response evaluations per RECIST v1.1.

Exclusion Criteria

• Any significant medical condition including any suggested by screening laboratory findings that, in the opinion of the Investigator or Sponsor, may place the subject at undue risk from the study.
• Uncontrolled cardiac disease (eg, symptomatic congestive heart failure, symptomatic coronary artery disease), myocardial infarction within the last 6 months, left ventricular ejection fraction (LVEF) < 45% as measured by ECHO.
• History of cardiac conduction abnormalities including: QT interval in electrocardiogram (ECG) corrected for heart rate using the Fridericia method (QTcF) interval > 470 msec, ECG with second degree type 2 or third degree atrioventricular block, left bundle branch block, or persistent bradycardia (as defined by sinus rate < 45 beats per minute), or persistent tachycardia (as defined by sinus rate > 120 beats per minute).
• Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional class system.
• Evidence of complete or partial bowel obstruction.
• Grade 2 or higher pleural or pericardial effusion within 4 weeks of initiation of study treatment, or earlier history of recurrent Grade 2 or higher pleural or pericardial effusion with ongoing requirement for thoracentesis or pericardiocentesis
  • NOTE: Subjects with trace physiologic pericardial effusions will be allowed.
• Subject has a history of uncontrolled ascites, or requires paracentesis more than once within 28 days prior to initiation of study treatment.
• Recent or ongoing serious infection, including:
  • Any active Grade 3 or higher viral, bacterial, or fungal infection within 2 weeks of the first dose of the study drug (routine antimicrobial prophylaxis is permitted);
  • Known seropositivity for or active infection by human immunodeficiency virus (HIV);
  • Active hepatitis B with surface antigen (HBsAg) positive or core antibody positive with viremia; or hepatitis C virus (HCV) antibody positive with viremia or on hepatitis-related antiviral therapy within 6 months of first dose of study drug.
• Female subject who is pregnant, breastfeeding, or is considering becoming pregnant during the study or for approximately 6 months after the last dose of study drug.
• Systemic therapy with corticosteroids at >20 mg/day prednisone or equivalent within 1 week prior to the first dose of study drug.
• History of prior malignancy, with the exception of the following:
  • Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years prior to screening and felt to be at low risk for recurrence by treating physician;
  • Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer;
  • Adequately treated cervical carcinoma in situ without current evidence of disease.
• Prior exposure to a pyrrolobenzodiazepine- or indolinobenzodiazepine-based drug, or known hypersensitivity or contraindication to SC-004 or excipient contained in the drug formulation. Includes potential subject with a history of major immunologic reaction to any IgG-containing agent.

Additional Exclusion Criteria for the SC-004 and ABBV-181 Combination Treatment Regimen

• History of inflammatory bowel disease.
• Peripheral neuropathy Grade 2 with pain, or Grade 3 or higher
• Creatinine clearance (CrCl) <40 mL/minute (using MDRD formula) .
• Subjects who have been previously treated with an anti-PD-1/PD-L1 targeting agent must not have had any of the following during the course of their therapy:
  • Any prior history of immune-mediated pneumonitis, regardless of grade, based on NCI CTCAE v.4.03;
  • Any immune-mediated toxicity of Grade 3 or worse severity;
  • Treatment for immune-related AE with systemic corticosteroids;
  • Any hypersensitivity to PD-1/PD-L1 targeting agents.
• Subject is judged by the Investigator to have evidence of ongoing hemolysis (assessment may be based on total, direct, and unconjugated serum bilirubin, peripheral blood smear, D-dimers and/or serum haptoglobin). International normalized ratio (INR) >1.4 during screening, in the absence of anticoagulation.
• Current or prior use of immunosuppressive medication within 14 days prior to the first dose of study treatment. The following are exceptions to this criterion:
  • Intranasal, inhaled, topical steroids or local steroid injections (e.g., intra-articular injection);
  • Systemic corticosteroids at doses not to exceed 10 mg/day of prednisone or equivalent;
  • Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
• History of major immunologic reaction to any IgG-containing agent.
• History of major surgery ≤28 days prior to the first dose of study drug and the surgical wound is not fully healed .
• Active autoimmune disease, with exceptions of psoriasis not requiring systemic treatment, vitiligo, type 1 diabetes mellitus, and hypothyroidism.
• History of primary immunodeficiency, allogeneic bone marrow transplantation, solid organ transplantation, or previous clinical diagnosis of tuberculosis.
• Subject has received live vaccine within 28 days prior to the first dose of study drug. 
• Liver metastases with ≥ 50% liver involvement.