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

NCT03319628 | Active Not Recruiting Phase 1 FDA Drug

• 1 other identifier: XMT-1536-1
• Study Type: interventional
• Target: 523
• Locations: 1 country
• Sites: 1

Brief Summary

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) were enrolled in the expansion segment of this study. Patients with platinum-resistant, high-grade serous ovarian cancer were enrolled in the UPLIFT segment of this study. In addition to safety assessments, the pharmacokinetics of the drug were assessed along with ADC activity. A QTc sub-study was added for the UPLIFT cohort for a sub-set of sites.

Conditions

Platinum Resistant Ovarian Cancer; Non Small Cell Lung Cancer Metastatic

Outcome Measures

Primary Outcomes (5)

• DES: Maximum tolerated dose or recommended Phase 2 dose

  Evaluate adverse events and concomitant medication use after XMT-1536 (upifitamab rilsodotin) doses

  Up to 36 weeks, from the date of first dose until unacceptable side effects or a dose-limiting toxicity is met

• DES and EXP: Safety and Tolerability

  Evaluate incidence and severity of adverse events

  First dose up until 30 days after study termination

• EXP: Anti-neoplastic effects of XMT-1536 (upifitamab rilsodotin)

  Monitor tumor size

  Every 6 weeks for up to 36 weeks

• UPLIFT: Investigator-assessed objective response rate (ORR) of XMT-1536 (upifitamab rilsodotin) in the ITT-Higher NaPi2b population

  Confirmed ORR is defined as the proportion of patients who have achieved a confirmed complete response (CR) or partial response (PR) per RECIST v1.1 after the initiation of study treatment.

  Every 8 weeks until disease progression or up to 24 months

• QTc Sub-study: Evaluation of the concentration response analysis of XMT-1536 versus the change in QTcF values

  "The concentration-QTcf change from baseline deltaQTcF analysis and analysis of central tendency for deltaQTcF

  60 minutes prior to first dose, up to 26 hours after Cycle 3 dose

Secondary Outcomes (11)

• DES and EXP: Time of maximum observed concentration of XMT-1536 (upifitamab rilsodotin)

  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

• DES and EXP: Maximum concentration of XMT-1536 (upifitamab rilsodotin)

  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

• DES and EXP: Area under the concentration curve of the last measurable concentration of XMT-1536 (upifitamab rilsodotin)

  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

• DES: Anti-neoplastic effects of XMT-1536 (upifitamab rilsodotin)

  Every 6 weeks for up to 36 weeks

• DES and EXP: Anti-drug antibody and neutralizing antibody

  Every 6 weeks for up to 36 weeks

Study Arms (5)

Dose Escalation

EXPERIMENTAL

XMT-1536 (upifitamab rilsodotin) treatment is administered in groups of patients who will receive doses that increase over time. This cohort is closed to enrollment.

Drug: upifitamab rilsodotin

Dose Expansion - Ovarian Cancer

EXPERIMENTAL

Once 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. This cohort is closed to enrollment.

Drug: upifitamab rilsodotin

Dose Expansion - NSCLC adenocarcinoma

EXPERIMENTAL

Once 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. This cohort is closed to enrollment.

Drug: upifitamab rilsodotin

Pivotal Cohort (UPLIFT)

EXPERIMENTAL

Patients with platinum-resistant ovarian cancer will receive XMT-1536 (upifitamab rilsodotin) to further confirm the efficacy. This cohort is closed to enrollment.

Drug: upifitamab rilsodotin

QTc Sub-Study

EXPERIMENTAL

For sites participating in the sub-study, patients with platinum -resistant ovarian cancer will have the option to enroll in this sub-study to evaluate potential changes in the QTc interval following administration of XMT-1536. This cohort is closed to enrollment.

Drug: upifitamab rilsodotin

Interventions

upifitamab rilsodotin DRUG

XMT-1536 will be administered once every 28 days until disease progression, unacceptable toxicity, or either the patient or study physician determines it is in the best interest of the patient to discontinue participation in the study. For sites participating in the sub-study, patients with platinum -resistant ovarian cancer will have the option to enroll in this sub-study to evaluate potential changes in the QTc interval following administration of XMT-1536

Also known as: XMT-1536, UpRi

Dose Escalation; Dose Expansion - NSCLC adenocarcinoma; Dose Expansion - Ovarian Cancer; Pivotal Cohort (UPLIFT); QTc Sub-Study

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• Absolute neutrophil count (ANC) ≥1500 cells/mm3
• Platelet count ≥100,000/mm3
• Hemoglobin ≥9 g/dL
• In patients not on anticoagulation therapy: INR, activated partial thromboplastin time (aPTT), and prothrombin time (PT) all within 1.2 times the institution's upper limit of normal (ULN). Patients on anticoagulation therapy are allowed if their relevant laboratory values are within the therapeutic window.
• Estimated glomerular filtration rate (GFR) ≥45 mL/min
• Total bilirubin ≤ULN
• g. 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.
• Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ≤1.5 times the institutional ULN.
• Albumin ≥3.0 g/dL
• Able to provide informed consent.

You may not qualify if:

• 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.
• 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.
• Current use of either constant or intermittent supplementary oxygen therapy.
• History of suspected 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 3A inhibitors or inducers that cannot be discontinued while receiving study treatment
• Oxygen saturation on room air \<93%
• 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

Sponsors & Collaborators

• Mersana Therapeutics: lead

Study Sites (1)

University of Oklahoma

Oklahoma City, Oklahoma, 73104, United States

Location

Study Officials

• Robert Burger, MD

  Mersana Therapeutics

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open-label, dose escalation to reach MTD. The MTD will be confirmed in parallel cohorts: patients with platinum-resistant ovarian cancer; patients with non-squamous NSCLC, adenocarcinoma subtype

Study Record Dates

• First Submitted: October 17, 2017
• First Posted: October 24, 2017
• Study Start: December 12, 2017
• Primary Completion: May 31, 2023
• Study Completion: October 31, 2024
• Last Updated: November 13, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)