MC# 20-09 - A Phase Ib, First-in-Human, Dose Escalation and Expansion Study of XMT-1592 In Patients with Solid Tumors Likely to Express NaPi2b

  • Agent(s): XMT-1592
  • Disease Type(s): Ovarian, Lung-NSCLC
  • Phase(s): I
  • Drug Classification(s): Antibody Drug Conjugate
  • Molecular Target(s): NaPi2b

Mechanism of Action

XMT-1592 is an antibody-drug conjugate targeting the sodium-phosphate transporter NaPi2b using an auristatin payload.

Purpose

In this study, the sponsor and investigators want to learn:

  • About the safety and tolerability of XMT-1592
  • How proteins that indicate the status of your disease are affected with use of XMT-1592
  • If the study agent prevents or delays tumor growth or shrinks existing tumors
  • How quickly XMT-1592 is removed from the blood stream
  • If the NaPi2b receptors allow for a greater uptake of XMT-1592
Inclusion Criteria
  • Documentation of histologically or cytologically confirmed solid tumors of the types specified below, with incurable, locally advanced or metastatic disease that has failed standard therapy or for which no standard treatment option exists:
    • Platinum-resistant, high-grade serous ovarian cancer (including epithelial ovarian, fallopian tube, and primary peritoneal cancer)
    • NSCLC, adenocarcinoma subtype
  • Females and males, age ≥ 18 years old
  • Eastern Cooperative Oncology Group (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)
  • 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/mm3
    • Platelet count ≥100,000/mm3
    • Hemoglobin ≥9 g/dL
    • International Normalized Ratio (INR), activated partial thromboplastin time (aPTT), and prothrombin time (PT) all within 1.2 times the institution’s upper limit of normal (×ULN) in the absence of any other indicator of liver dysfunction
    • Glomerular filtration rate (GFR) ≥45 mL/min
    • 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 after discussion with the Sponsor Medical Monitor
    • AST, ALT, and gamma glutamyl transferase (GGT) ≤1.5×ULN. ALP ≤1.5×ULN unless the elevation is clearly attributable to non-hepatic sources
    • Albumin ≥3.0 g/dL
  • Prophylactic transfusion of blood (or blood components) within 14 days prior to screening cannot be used to meet enrollment criteria.  Transfusion of blood (or blood components) to manage treatment-emergent anemia or other cytopenia is permissible and should be recorded as a concomitant medication.  Growth factor prophylaxis cannot be used prior to the first dose of XMT-1592. However, the use of growth factors as treatment for cytopenia is allowed.  Please contact the Medical Monitor if this is necessary.  If cytopenia occurs after administration of Cycle 1, use of growth factors may be administered prophylactically in subsequent cycles at the discretion of the Investigator and after consultation with the Medical Monitor.
  • Confirmed availability (prior to Cycle 1, Day 1) of archived tumor tissue blocks (strongly recommended) or freshly cut tissue slides from an archived sample.  Tissue specimens must be submitted within 45 days after the first dose of study drug.
  • Fresh tumor sample will be obtained if medically feasible.  If not medically feasible, enrollment without a fresh biopsy must be approved in writing by the Sponsor Medical Monitor.  Tissue specimens must be submitted within 45 days after the first dose of study drug.
  • For women of childbearing potential and men with partners of childbearing potential, agreement to use a highly effective form of hormonal contraception or 2 effective forms of non-hormonal contraception by the patient and/or partner, and to continue the use of contraception for the duration of study treatment and for at least 6 months after the last dose of study treatment
  • Able to sign informed consent

Inclusion Criteria – Dose Expansion: Ovarian Carcinoma

  • Histological diagnosis of high-grade serous ovarian, fallopian tube, or primary peritoneal cancer
  • One to 3 prior lines of systemic therapy for ovarian cancer including at least 1 prior line of a platinum-containing regimen.  Patients must have platinum-resistant disease, defined as progressing <180 days (patients who progressed >180 days may be enrolled upon written approval by the Sponsor Medical Monitor’s discretion) after the last platinum- based therapy.  Patients with 4 lines of prior systemic therapy may be enrolled at the Investigator’s discretion and upon written approval by the Sponsor Medical Monitor.
    • Maintenance therapy (e.g., a PARP-inhibitor or bevacizumab given after a platinum- containing regimen) will not count as a separate line of therapy
  • Tumor sample must be provided from both:
    • An archived tumor sample, and
    • A fresh tumor biopsy (if medically feasible)
    • If a fresh biopsy cannot be obtained, enrollment requires written approval by the Sponsor Medical Monitor

Inclusion Criteria – Dose Expansion: Non-small Cell Lung Cancer, Adenocarcinoma Subtype

  • Histological diagnosis of adenocarcinoma NSCLC, metastatic, locally advanced, or recurrent
  • One prior treatment regimen with a platinum-based (cisplatin or carboplatin) therapy and 1 prior treatment regimen with a PD-1 or PD-L1 mAb (either in combination or sequentially).  Patients previously treated with immunotherapy will require a washout phase of 4 weeks.  Potential autoimmune reactions (e.g. hypothyroidism, adrenal insufficiency) are required to be resolved/controlled (≤Grade 2).
  • Patients with known oncogenic mutations for which there are approved therapies (e.g., ALK translocation, EGFR mutation) must have received appropriate targeted therapy in addition to a platinum-based regimen.  Prior treatment with a PD1/L1 is not required for these patients.
  • Patient with up to 2 prior lines of chemotherapy for metastatic, locally advanced, or recurrent disease may be enrolled based on discretion of the Investigator and upon written approval from the Sponsor Medical Monitor
  • Head computerized tomography (CT) or magnetic resonance imaging (MRI) within 3 months prior to initiation of screening procedures
  • Tumor sample must be provided from both:
    • An archived tumor sample, and
    • A fresh tumor biopsy (if medically feasible)
    • If a fresh biopsy cannot be obtained, enrollment requires approval of the Sponsor Medical Monitor
Exclusion Criteria
  • Major surgery within 28 days of starting study treatment; or 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 (consultation with Medical Monitor is recommended)
  • Brain metastases that:
    • Are untreated
    • Are progressive
    • Have required any type of major treatment (e.g., whole brain radiation treatment, adjuvant chemotherapy, gamma knife) to control symptoms from brain metastases within 30 days of the first study treatment
    • Any history of leptomeningeal metastasis
  • Current use of antiretroviral therapy or known active infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).  In addition, negative serology is required during screening and at 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
    • HIV: Patients with a known history of HIV infection should have a CD4+ T-cell (CD4+) count ≥ 350 cells/µL to be eligible
  • Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease) or intercurrent illness that could interfere with per-protocol evaluations.  Further, patients are excluded with the following characteristics:
    • A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval > 480 milliseconds (ms) (CTCAE grade 1) 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)
    • The use of concomitant medications that prolong the QT/QTc interval
  • History of cirrhosis, hepatic fibrosis, varices, or other clinically significant liver disease.  FibroScan testing may be required for patients with a history of chronic liver disease (e.g., fatty liver).
    • For patients with a history of hepatotoxicity or significant liver enzyme elevation with prior therapy, discussion with Sponsor Medical Monitor is required before enrollment
    • Patients with a regular alcohol intake of more than 1 drink per day for women or more than 2 drinks today for men are not eligible, and alcohol consumption during trial participation should be discouraged
  • Patients cannot receive drugs associated with hepatotoxicity concurrent with XMT-1592 administration or for 21 days after the last dose of XMT-1592.  Patients may receive acetaminophen/paracetamol for a limited time but at a total daily dose of ≤2 g per day.  Use of non-steroidal anti-inflammatory drugs (NSAIDs) or steroids for treatment of fever is encouraged.
  • Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy
  • Currently active pneumonitis or interstitial lung disease related to prior oncology treatments.  Enrollment of patients with a history of pneumonitis must be approved by the Medical Monitor.
  • Pregnant or nursing women
  • Diagnosis of a second malignancy may be enrolled upon written approval by the Sponsor Medical Monitor
  • Active corneal disease, or history of corneal disease within 12 months prior to enrollment
  • Use of strong CYP450 inhibitors

Exclusion Criteria – Dose Expansion: Ovarian Carcinoma

  • Low-grade, clear cell, endometrioid, mucinous, carcinosarcoma, germ-cell, or stromal tumors
  • Prior treatment with mirvetuximab soravtansine or another ADC containing auristatin or maytansinoid payload
  • More than 2 prior lines of treatment with a taxane-containing regimen
  • Primary platinum resistant disease, defined by a lack of response or progression within 2 months after completing front-line, platinum-containing therapy
  • Participation in the DES segment of the study

Exclusion Criteria – Dose Expansion: Non-small Cell Lung Cancer, Adenocarcinoma Subtype

  • Histologies other than adenocarcinoma (e.g., large cell, squamous cell, or adenosquamous)
  • Prior treatment with an ADC containing auristatin or maytansinoid payload
  • More than 1 prior line of treatment with a chemotherapy agent in metastatic, locally advanced, or recurrent disease.  Patients with >1 prior line of therapy with a cytotoxic regimen may be enrolled upon written approval from the Sponsor Medical Monitor.
  • More than 1 prior line of immunotherapy
  • Participation in the DES segment of the study

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City

Contact Us About This Trial

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Re: MC# 20-09