MC# 19-05 - A Phase Ib/II, First-in-Human, Dose Escalation and Expansion Study of XMT-1536 In Patients with Solid Tumors Likely to Express NaPi2b

  • Agent(s): XMT-1536
  • Disease Type(s): Ovarian
  • Phase(s): I
  • Drug Classification(s): Antibody Drug Conjugate
  • Molecular Target(s): NaPi2b

Mechanism of Action

XMT-1536 is an anti-NaPi2b ADC conjugated to XMT-1535, a novel humanized anti-NaPi2b antibody, via the Dolaflexin ADC platform.

Purpose

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

  • About the safety and tolerability of XMT-1536
  • How much of XMT-1536 is absorbed into the blood and how fast it is removed
  • How proteins that indicate the status of your disease are affected with use of XMT-1536
  • If your body develops proteins that work against XMT-1536
  • If XMT-1536 prevents or delays tumor growth or shrinks an existing tumor
  • If the amount of NaPi2b (a protein on the surface of the cells of your tumor) on tumor cells can indicate how well XMT-1536 works at the cellular level
Inclusion Criteria
  • Must be 18 years or older
  • 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
  • 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

Ovarian Inclusion for UPLIFT - Cohort 3

  • 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)],
      • 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
    • 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
  • 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

Inclusion Criteria for QTc Sub-study

  • Study patient has agreed to remain in the clinic longer on the Day 1 of Cycle 1 and Cycle 3 (approximately 4-6 hours following XMT-1536 administration)
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 -or- recent radiation therapy with unresolved toxicity
  • Brain metastases that:
    • Are untreated
    • Are progressive
    • Or 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
    • Or any history of leptomeningeal metastasis
  • Current known active infection with HIV, hepatitis B virus, or hepatitis C virus
  • No prior history of liver disease such as liver cirrhosis, hepatic fibrosis
  • 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 (in unclear cases, consultation with the Medical Monitor is
    recommended).
  • History of cirrhosis, hepatic fibrosis, esophageal or gastric varices, or other clinically significant liver disease
  • 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
  • Participation in the DES segment of the study

Ovarian Exclusion for UPLIFT - Cohort 3

  • 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

Exclusion Criteria for QTc Sub-study

  • Use of strong CYP3A4 inducers dosed for systemic exposure 7 days prior to the first dosing and through to Day 9
  • Uncontrolled cardiac arrhythmias, for example, atrial fibrillation with a ventricular response at rest > 100 beats per minute. left bundle branch block (LBBB)
  • Known abnormality of any cardiac valve (either stenosis or regurgitation) that is greater than moderate in severity
  • Subjects not in sinus rhythm at screening with HR >45- <100
  • Any ECG abnormality that can interfere with the measurement of the QT interval

Location

  • Dallas, TX - Mary Crowley Cancer Research - Medical City
More Info: https://clinicaltrials.gov/ct2/show/NCT03319628

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Re: MC# 19-05