Ensayos clínicos

Inclusion Criteria:

• Females and males, aged ≥ 18 years old.
• ECOG performance status 0 or 1.
• Measurable disease as per RECIST, version 1.1.
• Resolution of all acute toxic effects of prior therapy or surgical procedures to ≤Grade 1 except alopecia, stable immune-related toxicity such as hypothyroidism on hormone replacement, adrenal insufficiency on ≤ 10m daily prednisolone (or equivalent), chronic Grade 2 peripheral sensory neuropathy after prior taxane therapy.
• Cardiac left ventricular ejection fraction (LVEF) ≥ 50% or ≥ the institution’s lower limit of normal by either Echo or MUGA scan.
• Adequate organ function as defined by the following criteria:
  • Absolute neutrophil count (ANC) ≥ 1500 cells/mm^3;
  • Platelet count ≥100,000/mm^3;
  • Hemoglobin ≥ 9 g/dLP;
  • In patients not on anticoagulation therapy: INR, activated partial thromboplastin time (aPTT), and prothrombin time (PT) all within 1.2 times the institutional upper limit of normal (ULN). Patients on anticoagulation therapy are allowed if their relevant laboratory values are within the therapeutic window;
  • Estimated glomerular filtration rate (GFR) ≥ 45 mL/minP;
  • Total bilirubin ≤ ULN;
  • Patients with asymptomatic elevations in unconjugated bilirubin due to Gilbert syndrome or stable chronic hemolytic anemia (e.g, hereditary spherocytosis, sickle cell disease, thalassemia intermedia) may be eligible.
• Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ≤ 1.5 times the institutional ULN.
• Albumin ≥ 3.0 g/dL.
• During the study, female study participants of child-bearing potential must use a highly effective non-hormonal form of contraception for the duration of study drug administration and for at least 6 months after the last dose of study drug. 
• Male study participants must use barrier contraception (condoms) for the duration of study drug and for at least 6 months after the last dose of study drug. The WOCBP partners of male study participants must use highly effective contraception for the duration of study drug and for at least 6 months after the last dose of study drug.
• Able to provide informed consent.

Exclusion Criteria:

• Major surgery within 28 days of starting study treatment, systemic anti-cancer therapy within the lesser of 28 days or 5 half-lives of the prior therapy before starting study treatment (14 days or 5 half-lives for small molecule targeted therapy), or recent radiation therapy with unresolved toxicity or within a time window of potential toxicity.
• Patients with untreated CNS metastases (including new and progressive brain metastases), history of leptomeningeal metastasis or carcinomatous meningitis. 
  • Patients are eligible if CNS metastases are adequately treated, and patients are neurologically stable for at least 2 weeks prior to enrollment;
  • In addition, patients must be either off corticosteroids, or on a stable/decreasing dose of ≤10 mg daily prednisone (or equivalent). Anticonvulsants are allowed except for those drugs associated with liver toxicity.
• Untreated, known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). In addition, negative serology is required during screening (baseline) for HBV and HCV:
  • HBV: Patients with serologic evidence of chronic HBV infection should have an HBV viral load below the limit of quantification to be eligible;
  • HCV: Patients with a history of HCV infection should have completed curative antiviral treatment and HCV viral load below the limit of quantification;
  • Screening for HIV is not required except if mandated by local regulations or indicated based on clinical assessment.
• Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease) or intercurrent illness that could increase risk of adverse events, whether or not potentially related to study treatment. Further, patients are excluded with the following characteristics:
  • A baseline prolongation of QTcF interval > CTCAE G1: repeated demonstration of a QTcF interval > 480 milliseconds (ms) using Frederica's QT correction formula;
  • A history of additional risk factors for Torsade's de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
• History of cirrhosis, hepatic fibrosis, esophageal or gastric varices, or other clinically significant liver disease. Testing beyond laboratory studies otherwise defined in the eligibility criteria, to diagnose potentially clinically significant liver disease based on risk factors such as hepatic steatosis or history of excessive alcohol intake, will be based on clinical judgement of the investigator.
• Patients cannot receive drugs associated with hepatotoxicity concurrent with XMT-1536 administration (refer to Appendix 4). Patients may receive acetaminophen/paracetamol for a limited time but at a total daily dose of ≤ 2 g per day. Use of NSAIDs or steroids for treatment of fever is encouraged.
• Current use of either constant or intermittent supplementary oxygen therapy.
• History of or suspected pneumonitis or interstitial lung disease.
• Oxygen saturation on room air < 93%.
• Pregnant or nursing women.
• Diagnosis of additional malignancy that progressed or required active treatment within the last 2 years, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix.
• Active corneal disease, or history of corneal disease within 12 months prior to enrollment.
• Use of strong CYP450 inhibitors.
• Known sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation
• Ovarian Cancer Inclusion Criteria for UPLIFT:
• Histological diagnosis of high grade serous ovarian cancer, which includes fallopian tube, or primary peritoneal cancer, that is metastatic or recurrent.
• Platinum-resistant disease:
  • Patients who have only had 1 line of platinum-based therapy must meet all of the below criteria: have received at least 4 cycles of platinum-containing chemotherapy, have had a response [complete response/remission (CR) or partial response/remission (PR)], and have progressed between 3 months and ≤ 6 months after the date of the last dose of platinum;
  • Patients who have received 2 to 4 lines of prior platinum-based therapy must have received at least 4 cycles of platinum-containing chemotherapy within their last platinum-based regimen and then progressed within 6 months after the date of the last dose of platinum.
    • Note: Progression should be calculated from the date of the last administered dose of platinum therapy to the date of the radiographic image showing progression. Patients who progressed within 3 months of front-line platinum-based therapy are excluded. If radiographic progression was not documented, the date of progression based on biopsy can be used for calculation.
• One to 4 prior lines of systemic therapy for ovarian cancer:
  • Prior treatment with bevacizumab is required for patients with 1 to 2 prior lines of therapy;
  • In France, patients must have received at least 2 lines of systemic therapy and must not be candidates for surgery.
  • Definitions for prior lines of therapy:
    • Adjuvant ± neoadjuvant considered one line of therapy as long as they are the same regimens (e.g., platinum/taxane for 4 cycles before surgery followed by platinum/taxane for 4 cycles after surgery);
    • Maintenance therapy (e.g., bevacizumab, PARPi, endocrine therapy) will be considered as part of the preceding line of therapy (i.e., not counted independently);
    • Therapy given for only 1 cycle and discontinued due to toxicity in the absence of progression will not be counted as a new line of therapy; therapy given for 2 or more cycles will be counted as a line of therapy. Substitutions of different platinum agents or taxanes will not be counted as new lines;
    • Hormonal therapy (e.g., tamoxifen, letrozole) will be counted as a separate line of therapy unless it was given as maintenance.
  • In Sweden, patients must have received prior treatment with pegylated liposomal doxorubicin or paclitaxel, if not contraindicate.
• Patients must be willing to provide an archival tumor tissue block or slides or if not available, undergo procedure to obtain a new tumor biopsy using a low-risk, medically routine procedure.
• Ovarian Cancer Exclusion Criteria for UPLIFT:
  • Low-grade, clear cell, endometrioid, mucinous, carcinosarcoma, germ-cell, mixed histology, or stromal tumors;
  • Prior treatment with mirvetuximab soravtansine or another ADC containing an antitubulin payload;
  • Lack of response to front-line, platinum-containing therapy or progression less than 3 months after completing front-line, platinum-containing therapy;
  • Participation in DES or EXP segments of this study.

Eligibility last updated 12/7/21. Questions regarding updates should be directed to the study team contact.