| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High grade serous ovarian cancer or non-small cell lung cancer (NSCLC), adenocarcinoma subtype |
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| E.1.1.1 | Medical condition in easily understood language |
| Ovarian cancer or non-small cell lung cancer. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033128 |
| E.1.2 | Term | Ovarian cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary in Dose Escalation (DES):
Determine the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of XMT-1536 administered intravenously once every 28 days
Assess the safety and tolerability of XMT-1536
Primary in Expansion (EXP):
Assess further safety and tolerability using the MTD or RP2D identified in DES
Assess the preliminary anti-neoplastic activity of XMT-1536
Primary in Pivotal Cohort (UPLIFT):
Determine the confirmed investigator-assessed objective response rate of XMT-1536 (upifitamab rilsodotin) at a starting dose level of 36 mg/m2 q4wk capped at 2.2 m2 in patients with higher (TPS ≥75) sodium-dependent phosphate transport protein 2b (NaPi2b) expressing platinum-resistant high-grade serous ovarian cancer (HGSOC), including cancers of ovarian, fallopian tube or primary peritoneal origin) |
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| E.2.2 | Secondary objectives of the trial |
Secondary in DES:
Assess preliminary anti-neoplastic activity of XMT-1536
Secondary in DES and EXP:
Assess PK, release product, selected metabolites, development of anti-drug antibodies and association of tumor expression of NaPi2b and objective tumor response to XMT-1536.
Assess safety and efficacy in ovarian cancer subpopulations, including patients previously treated and failed therapy with bevacizumab and patients with and without Breast Cancer type 1 susceptibility gene (BRCA) mutation who were previously treated and failed therapy with poly ADP ribose polymerase inhibitors (PARPi).
Secondary in UPLIFT:
Assess confirmed investigator-assessed objective response rate of XMT- 1536 regardless of NaPi2b expression.
Assess confirmed objective response rate by indep radiology review (IRR) for patients with high (TPS ≥75) NaPi2b and overall.
Assess duration of objective response (DOR) in patients who achieve a response.
Assess incidence and severity of adverse events.
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|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For Dose Escalation, Expansion and Uplift
1.Females and males, aged ≥18 years old
2.ECOG performance status 0 or 1
3.Measurable disease as per RECIST, version 1.1
4.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 [prednisolone] (or equivalent) chronic Grade 2 peripheral sensory neuropathy after prior taxane therapy).
5.Cardiac left ventricular ejection fraction (LVEF) ≥50% or ≥ the institution’s lower limit of normal by either Echo or MUGA scan
6. Adequate organ function as defined by the following criteria:
a. Absolute neutrophil count (ANC) ≥1500 cells/mm3
b. Platelet count ≥100,000/mm3
c. Hemoglobin ≥9 g/dLa
d.In patients not on anticoagulation therapy: 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 if their relevant laboratory values are within the therapeutic window.
e. Estimated glomerular filtration rate (GFR) ≥45 mL/min
f. Total bilirubin ≤ULN
Patients with asymptomatic elevations in unconjugated bilirubin due to Gilbert syndrome or stable chronic hemolytic anemia may be eligible after discussion with the Sponsor Medical Monitor.
7. Aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT) ≤1.5 times the institutional ULN.
8. Albumin ≥3.0 g/dL
9. Female 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.
Please see Appendix 7 of the Protocol for examples of non-hormonal highly effective contraceptive methods.
10.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 (Appendix 7.).
11. Able to provide informed consent
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| E.4 | Principal exclusion criteria |
For Dose Escalation, Expansion and Uplift
1. 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 (14 days or 5 half-lives for small molecule targeted therapy), or recent radiation therapy with unresolved toxicity or within a time window of potential toxicity (consultation with the Sponsor Medical Monitor is recommended).
2. Patients with untreated CNS metastases (including new and progressive brain metastases), history of leptomeningeal metastasis or carcinomatous meningitis.
a. Patients are eligible if CNS metastases are adequately treated and patients are neurologically stable for at least 2 weeks prior to enrollment.
b. In addition, patients must be either off corticosteroids, or on a stable/decreasing dose of ≤ 10 mg daily prednisone (or equivalent). Anticonvulsants are allowed except for those drugs associated with liver toxicity.
3. Untreated known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). In addition, negative serology is required during screening (baseline) for HBV and HCV:
a. HBV: Patients with serologic evidence of chronic HBV infection should have an HBV viral load below the limit of quantification to be eligible.
b. HCV: Patients with a history of HCV infection should have completed curative antiviral treatment and HCV viral load below the limit of quantification.
c. HIV: screening for HIV is not required except if mandated by local regulations or indicated based on clinical assessment.
4. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease) or intercurrent illness that could risk of adverse events, whether or not potentially related to study treatment (in unclear cases, consultation with the Medical Monitor is recommended). Further, patients are excluded with the following characteristics:
a. A marked baseline prolongation of QT/QTcQTcF interval >CTCAE G1: repeated demonstration of a QTcF interval >480 milliseconds (ms) using Frederica's QT correction formula.
b. A history of additional risk factors for Torsade's de Pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
5. History of cirrhosis, hepatic fibrosis, esophageal or gastric varices, or other clinically significant liver disease. FibroScan testing may be required for patients with a history of chronic liver disease, e.g., fatty liver. Testing beyond laboratory studies otherwise defined in the eligibility criteria, to diagnose potentially clinically significant liver disease based on risk factors such as hepatic steatosis or history of excessive alcohol intake, will be based on clinical judgement of the investigator.
6. Patients cannot receive drugs associated with hepatotoxicity concurrent with XMT-1536 administration. Patients may receive acetaminophen/paracetamol for a limited time but at a total daily dose of ≤2 g per day. Use of NSAIDs or steroids for treatment of fever is encouraged.
7. Current use of either constant or intermittent supplementary oxygen therapy.
8. History of or suspected pneumonitis, or interstitial lung disease
9. Oxygen saturation on room air <93%.
10. Pregnant or nursing women
11.Diagnosis of additional malignancy that progressed or required active treatment within at least 2 years , except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix
12. Active corneal disease, or history of corneal disease within 12 months prior to enrollment.
13. Use of strong CYP450 3A inhibitors or inducers that cannot be discontinued while
receiving study treatment.
14.Known sensitivity to any of the study medications, or components thereof, or a history of drug or other allergy that, in the opinion of the investigator or Medical Monitor, contraindicates their participation.
15.In the Czech Republic, patients cannot be enrolled if they have received a live/attenuated vaccine within 30 days of study entry or if they plan to receive a live/attenuated vaccine while on treatment through 90 days post the last dose of study medication.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
For dose escalation:
-Maximum Tolerated Dose (MTD)
-Recommended Phase 2 dose (RP2D)
-Safety and Tolerability Measures
For dose expansion
-Safety and Tolerability Measures
-Objective Response Rate (ORR)
-Disease Control Rate (DCR)
For UPLIFT:
Confirmed investigator-assessed ORR in the ITT-NaPi2b Positive (≥75) population
(Positive [≥75]and negative NaPi2b [<75] status will have been defined prior to sample testing and based on data from a separate subject group.)
Objective Response Rate (ORR) in the ITT-Higher NaPi2b population
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
For dose escalation:
MTD: assessed once at the end of dose escalation.
RP2D: assessed once at the end of dose escalation.
Safety and Tolerability Measures: evaluated at every patient visit.
For dose expansion:
Safety and Tolerability Measures: evaluated at every patient visit.
ORR: measured once at the end of study using a composite of RECIST evaluations that are compared to each patient’s baseline measurement and subsequent post exposure to XMT-1536.
DCR: determined once at the end of the study by adding CR+PR+SD based on the best overall response for the study.
For UPLIFT:
- measured once at the end of study using a composite of RECIST
evaluations that are compared to each patient's baseline measurement and subsequent post exposure to XMT-1536.
|
|
| E.5.2 | Secondary end point(s) |
For dose escalation:
Objective response rate (ORR)
Duration of response (DOR)
Disease control rate (DCR) = CR + PR + SD (any duration)
PK profile of XMT-1536, its release product, and metabolites
Anti-drug antibody levels and nAb levels
NaPi2b protein or RNA levels measured in tumor samples
For dose expansion:
PK profile of XMT-1536, its release product, and metabolites
Anti-drug antibody levels and nAb levels NaPi2b protein or RNA levels measured in tumor samples
Analyze the effect of NaPi2b expression on objective response
DOR, PFS, OS
Sub-group analyses of responses in ovarian cancer patients including patients
previously treated and failed therapy with bevacizumab and patients with and without BRCA mutation who were previously treated and failed therapy with PARP inhibitors.
Uplift:
Confirmed investigator-assessed ORR in the entire ITT population
ORR by IRR in the ITT-Higher NaPi2b population; ORR by IRR in the entire ITT population
DOR in the ITT-Higher NaPi2b population
DOR in the entire ITT population
Safety and tolerability measures |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
For dose escalation:
- ORR: see E.5.1.1
- DCR: see E.5.1.1
For dose expansion:
- DOR, PFS, OS: end of study/patient last contact with site
- Sub-group analyses of responses: end of study
- NaPi2b expression: tumor samples collected at study entry and no later than 20 days after first dose
For dose escalation & expansion:
- ADA & nAB: Samples collected pre-first dose during Screen, pre-dose in Cycles 2, 3, 4 and all even number cycles after. ADA positive samples to be tested for nAB
- NaPi2b protein or RNA levels: Biopsies obtained prior to first dose and at end of treatment
- PK: Cycle 1 & 3: PK samples collected at Cycle 1 pre-dose, EOI, EOI+4, EOI+6, and at each visit after. Cycles 2, 4 and subsequent cycles: PK samples collected pre-dose, EOI and at each visit after
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| New Zealand |
| United States |
| Austria |
| Estonia |
| Finland |
| France |
| Lithuania |
| Poland |
| Sweden |
| Bulgaria |
| Spain |
| Italy |
| Belgium |
| Denmark |
| Norway |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Subjects will have an End of Treatment Visit (LSLV) and thereafter will be followed for survival via telephone calls every 3 months. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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