Clinical Trials /

First-in-Human Study of XMT-1536 in Cancers Likely to Express NaPi2b

NCT03319628

Description:

First-in-human, Phase 1b/2 safety study of the antibody-drug conjugate (ADC) XMT-1536 (upifitamab rilsodotin) administered as an intravenous infusion once every four weeks. Patients with tumor types likely to express NaPi2b were enrolled in dose escalation. Patients with platinum-resistant ovarian cancer and non-small cell lung cancer (adenocarcinoma subtype) are being enrolled in the expansion segment of this study. Patients with platinum-resistant, high-grade serous ovarian cancer are being enrolled in the UPLIFT segment of this study. In addition to safety assessments, the pharmacokinetics of the drug will be assessed along with ADC activity.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Non-Small Cell Lung Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: First-in-Human Study of XMT-1536 in Cancers Likely to Express NaPi2b
  • Official Title: A Phase 1b/2, First-in-Human, Dose Escalation and Expansion Study of XMT-1536 In Patients With Solid Tumors Likely to Express NaPi2b

Clinical Trial IDs

  • ORG STUDY ID: XMT-1536-1
  • NCT ID: NCT03319628

Conditions

  • Platinum Resistant Ovarian Cancer
  • Non Small Cell Lung Cancer Metastatic

Interventions

DrugSynonymsArms
upifitamab rilsodotinXMT-1536, UpRiDose Escalation

Purpose

First-in-human, Phase 1b/2 safety study of the antibody-drug conjugate (ADC) XMT-1536 (upifitamab rilsodotin) administered as an intravenous infusion once every four weeks. Patients with tumor types likely to express NaPi2b were enrolled in dose escalation. Patients with platinum-resistant ovarian cancer and non-small cell lung cancer (adenocarcinoma subtype) are being enrolled in the expansion segment of this study. Patients with platinum-resistant, high-grade serous ovarian cancer are being enrolled in the UPLIFT segment of this study. In addition to safety assessments, the pharmacokinetics of the drug will be assessed along with ADC activity.

Detailed Description

      This is a multi-center study of XMT-1536 (upifitamab rilsodotin) in patients with tumors
      likely to express NaPi2b, focusing on patients with platinum-resistant ovarian cancer and
      non-small cell lung cancer, adenocarcinoma subtype. XMT-1536 (upifitamab rilsodotin) will be
      administered as an intravenous infusion once every four weeks. The study consists of three
      segments: dose escalation (DES), dose expansion (EXP), and the pivotal cohort (UPLIFT). The
      DES segment studied small groups of patients who received increased doses. A Safety Review
      Committee was established to review the data from each dose level before moving to the next
      higher dose. The dose escalation cohort has ended and is no longer enrolling patients.
      Enrollment into the EXP segment consists of 2 parallel cohorts of patients to confirm the
      dose that has been identified in DES and estimate the objective response rate in each patient
      population. Enrollment into the pivotal cohort (UPLIFT) includes patients with
      platinum-resistant ovarian cancer. All adverse events will be graded according to the
      National Cancer Institute (NCI) Common Terminology Criteria version (CTCAE v5.0). Throughout
      the study, pharmacokinetics will be measured using proprietary assays developed by Mersana.
      Anti-cancer activity will be measured via RECIST.
    

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalXMT-1536 (upifitamab rilsodotin) treatment is administered in groups of patients who will receive doses that increase over time. This cohort is closed to enrollment.
  • upifitamab rilsodotin
Dose Expansion - Ovarian CancerExperimentalOnce the maximum tolerated dose or recommended Phase 2 dose is achieved in dose escalation, new groups of patients will receive XMT-1536 (upifitamab rilsodotin) at this fixed-dose. Patients with ovarian cancer will enroll until sites approve UPLIFT.
  • upifitamab rilsodotin
Dose Expansion - NSCLC adenocarcinomaExperimentalOnce the maximum tolerated dose or recommended Phase 2 dose is achieved in dose escalation, new groups of patients will receive XMT-1536 (upifitamab rilsodotin) at this fixed-dose.
  • upifitamab rilsodotin
Pivotal Cohort (UPLIFT)ExperimentalPatients with platinum-resistant ovarian cancer will receive the recommended Phase 2 dose of XMT-1536 (upifitamab rilsodotin) to further confirm the efficacy
  • upifitamab rilsodotin

Eligibility Criteria

        General Inclusion Criteria (for Dose Escalation, Expansion, and UPLIFT):

          -  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 ≤10 mg daily prednisone [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:

               1. Absolute neutrophil count (ANC) ≥1500 cells/mm3

               2. Platelet count ≥100,000/mm3

               3. Hemoglobin ≥9 g/dL

               4. INR, activated partial thromboplastin time (aPTT), and prothrombin time (PT) all
                  within 1.2 times the institutional upper limit of normal (ULN) in the absence of
                  any other indicator of liver dysfunction. Patients on anticoagulants are allowed.

               5. Estimated glomerular filtration rate (GFR) ≥45 mL/min

               6. Total bilirubin ≤ULN

          -  Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT)
             ≤1.5 times the institutional ULN. Alkaline phosphatase (ALP) ≤1.5 times ULN unless
             clearly attributable to a non-hepatic source, e.g., bone metastasis.

          -  Albumin ≥3.0 g/dL

          -  Able to provide informed consent.

        General Exclusion Criteria (for Dose Escalation, Expansion, and UPLIFT) :

          -  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, 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.

          -  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.

          -  Pregnant or nursing women.

          -  History of other malignancy within the last 2 years, except for appropriately treated
             carcinoma in situ of the cervix, non-melanoma skin carcinoma, or other malignancy with
             a similar expected curative outcome.

          -  Active corneal disease, or history of corneal disease within 12 months prior to
             enrollment

          -  Use of strong CYP450 inhibitors

        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

               1. 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

               2. 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

          -  One to 4 prior lines of systemic therapy for ovarian cancer

             a. Prior treatment with bevacizumab is required for patients with 1 to 2 prior lines
             of therapy

          -  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

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

          -  Participation in DES or EXP segments of this study

        Ovarian Cancer Inclusion Criteria 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 3 prior lines of systemic therapy for ovarian cancer including at least 1 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.

               1. 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.

               2. 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.

               1. An archived tumor sample

               2. A recent tumor biopsy (if medically feasible). If a recent biopsy cannot be
                  obtained, enrollment requires written approval by the Sponsor Medical Monitor.

        Ovarian Cancer Exclusion Criteria for Expansion:

          -  Low-grade, clear cell, endometrioid, mucinous, carcinosarcoma, germ-cell, or stromal
             tumors

          -  Prior treatment with mirvetuximab soravtansine or another ADC containing an 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

          -  Participation in the dose escalation segment of this study

        NSCLC Inclusion Criteria 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).

             a. Patients previously treated with immunotherapy will require a washout phase of 4
             weeks

          -  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

          -  Head CT or MRI within 3 months prior to initiation of screening procedures or may be
             done during screening

             a. Patients with history of brain metastases must have brain imaging within 4 weeks
             prior to or during screening

          -  Tumor sample must be provided from both timepoints.

               1. An archived tumor sample

               2. A recent tumor biopsy (if medically feasible)

        NSCLC Exclusion Criteria 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

          -  Participation in the dose escalation segment of this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:DES: Maximum tolerated dose or recommended Phase 2 dose
Time Frame:Up to 36 weeks, from the date of first dose until unacceptable side effects or a dose-limiting toxicity is met
Safety Issue:
Description:Evaluate adverse events and concomitant medication use after XMT-1536 (upifitamab rilsodotin) doses

Secondary Outcome Measures

Measure:DES and EXP: Time of maximum observed concentration of XMT-1536 (upifitamab rilsodotin)
Time Frame:Daily for one week after first dose; weekly until 28 days after first dose; immediately before and after and 1 week after all subsequent doses
Safety Issue:
Description:Determine the pharmacokinetics of XMT-1536 (upifitamab rilsodotin)
Measure:DES and EXP: Maximum concentration of XMT-1536 (upifitamab rilsodotin)
Time Frame:Daily for one week after first dose; weekly until 28 days after first dose; immediately before and after and 1 week after all subsequent doses
Safety Issue:
Description:Determine the pharmacokinetics of XMT-1536 (upifitamab rilsodotin)
Measure:DES and EXP: Area under the concentration curve of the last measurable concentration of XMT-1536 (upifitamab rilsodotin)
Time Frame:Daily for one week after first dose; weekly until 28 days after first dose; immediately before and after and 1 week after all subsequent doses
Safety Issue:
Description:Determine the pharmacokinetics of XMT-1536 (upifitamab rilsodotin)
Measure:DES: Anti-neoplastic effects of XMT-1536 (upifitamab rilsodotin)
Time Frame:Every 6 weeks for up to 36 weeks
Safety Issue:
Description:Monitor tumor size
Measure:DES and EXP: Anti-drug antibody and neutralizing antibody
Time Frame:Every 6 weeks for up to 36 weeks
Safety Issue:
Description:Analyze blood for antibodies to XMT-1536 (upifitamab rilsodotin) and neutralizing antibodies
Measure:UPLIFT: Investigator-assessed objective response rate of XMT-1536 (upifitamab rilsodotin) regardless of NaPi2b expression
Time Frame:Every 8 weeks until disease progression or up to 24 months
Safety Issue:
Description:Assess the investigator-assessed objective response rate of XMT-1536 (upifitamab rilsodotin) regardless of NaPi2b expression
Measure:UPLIFT: Objective response rate by independent radiology review (IRR) for patients with higher NaPi2b and overall
Time Frame:Every 8 weeks until disease progression or up to 24 months
Safety Issue:
Description:Assess the objective response rate by IRR for patients with higher NaPi2b and overall
Measure:UPLIFT: Duration of objective response (DOR)
Time Frame:4 weeks after first response and every 8 weeks until disease progression or up to 24 months
Safety Issue:
Description:Assess the duration of objective response (DOR) in patients who achieve a response
Measure:UPLIFT: Incidence and severity of adverse events
Time Frame:First dose up until 60 days after study termination
Safety Issue:
Description:Evaluate incidence and severity of adverse events

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mersana Therapeutics

Last Updated

February 16, 2021