MC# 19-05 - A Phase Ib, 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 Expansion

  • Histological diagnosis of high-grade serous ovarian cancer, which includes fallopian tube, or primary peritoneal cancer that is metastatic or recurrent
  • One to three prior lines of systemic therapy for ovarian cancer including at least one prior line of a platinum-containing regimen.  These patients must have platinum-resistant disease, defined as completing 4 or more cycles of platinum-based therapy and progressing within 6 months of last platinum-based therapy.
    • Patients with 4 lines of prior systemic therapy regardless of platinum sensitivity status 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 timepoints
    • An archived tumor sample, and
    • A recent tumor biopsy (if medically feasible).  If a recent biopsy cannot be obtained, enrollment requires written approval by the Sponsor Medical Monitor.
      • A previous tumor tissue sample obtained after completion of the last treatment (e.g., to confirm disease progression) and before signing informed consent for this study may be submitted as the recent sample.  The patient must not have had any intervening therapy.

NSCLC Inclusion for Expansion

  • Histological diagnosis of adenocarcinoma NSCLC that is metastatic or recurrent
  • One prior treatment regimen with a platinum-based therapy and 1 prior treatment regimen with a PD-1 or PD-L1 monoclonal antibody (either in combination or sequentially).  Patients previously treated with immunotherapy will require a washout phase of 4 weeks.
    • Patients with a shorter wash out phase may be enrolled upon written approval from the Sponsor Medical Monitor
    • Potential autoimmune reactions are required to be resolved/controlled (such as hypothyroidism on hormone replacement, adrenal insufficiency on ≤10 mg daily prednisolone [or equivalent], chronic Grade 2 peripheral sensory neuropathy after prior taxane therapy)
  • 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
  • One or 2 prior lines of chemotherapy
    • Chemotherapy for non-metastatic disease (e.g. adjuvant therapy, definitive chemoradiation) does not count towards 2 prior lines of chemotherapy if at least 12 months have elapsed from last dose of chemotherapy to the first dose of therapy for metastatic/recurrent disease
  • Head CT or MRI within 3 months prior to initiation of screening procedures or may be done during screening
    • Patients with a known history of brain metastases should have brain imaging within 4 weeks prior to or during screening
  • Tumor sample must be provided from both timepoints
    • An archived tumor sample, and
    • A recent tumor biopsy (if medically feasible).  If a recent biopsy cannot be obtained, enrollment requires approval of the Sponsor Medical Monitor.
      • A previous tumor tissue sample obtained after completion of the last treatment (e.g., to confirm disease progression) and before signing informed consent for this study may be submitted as the recent sample.  The patient must not have had any intervening therapy.

Ovarian Inclusion 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 have received at least 4 cycles of platinum, must have had a response [complete response/remission (CR) or partial response/remission (PR)], and then 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 therapy must have received at least 4 cycles of platinum 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.
  • 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 changed due to toxicity in the absence of progression will be considered as part of the same line (i.e., not counted independently); therapy given for 2 or more cycles will be counted as a new line
      • Hormonal therapy (e.g., tamoxifen, letrozole) will be counted as a separate line of therapy unless it was given as maintenance
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 interfere with per-protocol evaluations
  • Severe dyspnea at rest due to complications of advanced malignancy, or requiring supplementary oxygen therapy
  • Currently active pneumonitis or interstitial lung disease or a history of Grade ≥ 2 pneumonitis within the last 2 months that required medical intervention such as treatment with corticosteroids
  • 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 Expansion

  • 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 3 months after completing front-line, platinum-containing therapy

NSCLC Exclusion for Expansion

  • Histologies other than adenocarcinoma, e.g., large cell, squamous cell, or adenosquamous
  • Prior treatment with an ADC containing auristatin or maytansinoid payload
  • More than one prior line of immunotherapy
    • Two immune checkpoint inhibitor regimen (i.e., ipilimumab plus nivolumab) count as one line
    • Immunotherapy given for maintenance or locally advanced stage III disease (e.g., consolidation therapy) does not count towards prior lines if at least 12 months have elapsed from last dose of immunotherapy to the first dose of therapy for metastatic/recurrent disease

Ovarian Exclusion 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
  • Primary platinum-resistant disease, defined by a lack of response or by progression within 3 months after completing front-line, platinum-containing therapy

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