First-in-Human Study of XMT-1536 in Cancers Likely to Express NaPi2b
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| ClinicalTrials.gov Identifier: NCT03319628 |
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Recruitment Status :
Recruiting
First Posted : October 24, 2017
Last Update Posted : January 25, 2023
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Platinum Resistant Ovarian Cancer Non Small Cell Lung Cancer Metastatic | Drug: upifitamab rilsodotin | Phase 1 Phase 2 |
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 444 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Parallel Assignment |
| Intervention Model Description: | 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 |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| 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 |
| Actual Study Start Date : | December 12, 2017 |
| Estimated Primary Completion Date : | April 30, 2023 |
| Estimated Study Completion Date : | December 31, 2024 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Dose Escalation
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
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 Other Names:
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Experimental: Dose Expansion - Ovarian Cancer
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
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 Other Names:
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Experimental: Dose Expansion - NSCLC adenocarcinoma
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
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 Other Names:
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Experimental: Pivotal Cohort (UPLIFT)
Patients with platinum-resistant ovarian cancer will receive XMT-1536 (upifitamab rilsodotin) to further confirm the efficacy
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Drug: upifitamab rilsodotin
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 Other Names:
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Experimental: QTc Sub-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.
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Drug: upifitamab rilsodotin
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 Other Names:
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- 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 ]Evaluate adverse events and concomitant medication use after XMT-1536 (upifitamab rilsodotin) doses
- DES and EXP: Safety and Tolerability [ Time Frame: First dose up until 30 days after study termination ]Evaluate incidence and severity of adverse events
- EXP: Anti-neoplastic effects of XMT-1536 (upifitamab rilsodotin) [ Time Frame: Every 6 weeks for up to 36 weeks ]Monitor tumor size
- UPLIFT: Investigator-assessed objective response rate (ORR) of XMT-1536 (upifitamab rilsodotin) in the ITT-Higher NaPi2b population [ Time Frame: Every 8 weeks until disease progression or up to 24 months ]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.
- QTc Sub-study: Evaluation of the concentration response analysis of XMT-1536 versus the change in QTcF values [ Time Frame: 60 minutes prior to first dose, up to 26 hours after Cycle 3 dose ]"The concentration-QTcf change from baseline deltaQTcF analysis and analysis of central tendency for deltaQTcF
- 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 ]Determine the pharmacokinetics of XMT-1536 (upifitamab rilsodotin)
- 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 ]Determine the pharmacokinetics of XMT-1536 (upifitamab rilsodotin)
- 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 ]Determine the pharmacokinetics of XMT-1536 (upifitamab rilsodotin)
- DES: Anti-neoplastic effects of XMT-1536 (upifitamab rilsodotin) [ Time Frame: Every 6 weeks for up to 36 weeks ]Monitor tumor size
- DES and EXP: Anti-drug antibody and neutralizing antibody [ Time Frame: Every 6 weeks for up to 36 weeks ]Analyze blood for antibodies to XMT-1536 (upifitamab rilsodotin) and neutralizing antibodies
- UPLIFT: Confirmed 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 ]Assess the confirmed investigator-assessed objective response rate of XMT-1536 (upifitamab rilsodotin) regardless of NaPi2b expression
- UPLIFT: Confirmed objective response rate by independent radiology review (IRR) for patients with high NaPi2b and overall [ Time Frame: Every 8 weeks until disease progression or up to 24 months ]Assess the confirmed objective response rate by IRR for patients with high NaPi2b (TPS >/=75) and overall
- 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 ]Assess the duration of objective response (DOR) in patients who achieve a response
- UPLIFT: Incidence and severity of adverse events [ Time Frame: First dose up until 60 days after study termination ]Evaluate incidence and severity of adverse events
- QTc Sub-Study: Evaluation of the effect of XMT-1536 on QTcF in patients with platinum-resistant HGSOC by timepoint analysis [ Time Frame: 60 minutes prior to first dose, up to 26 hours after Cycle 3 dose ]Con.-QTc evaluation
- QTc Sub-Study: Evaluation of the effect of XMT-1536 on the PR-interval (PR), QRS duration (QRS), Heart Rate (HR), and ECG morphology [ Time Frame: 60 minutes prior to first dose, up to 26 hours after Cycle 3 dose ]Con.-QTc evaluation
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
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
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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.
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.
- 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%
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.
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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
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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 QTc sub-study:
Note: patients must meet all UPLIFT cohort inclusion criteria in order to participate in the QTc sub-study
• Study patient has agreed to remain in the clinic for the additional QTc related study activities on the Day 1 of Cycle 1 and Cycle 3.
Ovarian Cancer Exclusion Criteria for QTc sub-study:
- Use of strong CYP450 3A inducers.
- 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
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03319628
| Contact: Jamie Barrett | 617-715-8214 | medicalinformation@mersana.com |
Show 172 study locations
| Study Director: | Leslie DeMars, MD | Mersana Therapeutics |
| Responsible Party: | Mersana Therapeutics |
| ClinicalTrials.gov Identifier: | NCT03319628 |
| Other Study ID Numbers: |
XMT-1536-1 |
| First Posted: | October 24, 2017 Key Record Dates |
| Last Update Posted: | January 25, 2023 |
| Last Verified: | January 2023 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |