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

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.

Inclusion 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

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 Phase Phase I/II

Trial Type Treatment

Lead Organization
Mersana Therapeutics

• Primary ID XMT-1536-1
• Secondary IDs NCI-2018-00402
• Clinicaltrials.gov ID NCT03319628