| 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 |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ovarian cancer or non-small cell lung cancer. |
|
| 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) in patients with higher 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) |
|
| 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 investigator-assessed objective response rate of XMT-1536 regardless of NaPi2b expression.
Assess objective response rate by indep radiology review (IRR) for patients with higher 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 prednisone [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. 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.
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. Alkaline phosphatase (ALP) ≤1.5 times ULN unless clearly attributable to a non-hepatic source, e.g., bone metastasis.
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.
Examples of non-hormonal highly effective contraceptive methods include:
a) intrauterine device (IUD)
b) bilateral tubal occlusion
c) vasectomized partner
d) female sterilization.
e) sexual abstinence
Sexual Abstinence is defined by refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence shall be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the study patient.
Periodic abstinence (calendar, symptom-thermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception
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
10. 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.
4. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease) or intercurrent illness that could interfere with per-protocol evaluations. Further, patients are excluded with the following characteristics:
a. A marked baseline prolongation of QT/QTc interval 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).
c. The use of concomitant medications that prolong the QT/QTc interval will be reviewed first with the Sponsor Medical Monitor.
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.
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. Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen therapy.
8. Currently active pneumonitis, interstitial lung disease, or a history of Grade ≥ 2 pneumonitis within the last 12 months that required medical intervention such as treatment with corticosteroids
9. Pregnant or nursing women
10.Diagnosis of additional malignancy that required treatment within 2 years prior to screening, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix
11. Active corneal disease, or history of corneal disease within 12 months prior to enrollment.
12. Use of strong CYP450 inhibitors
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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)
|
|
| 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. Scans are done after end of C2 and after every subsequent even numbered cycle i.e. C4, C6 etc.
- DCR: calculated by adding CR+PR+SD for all patients that have response at any given point DCR is calculated.
|
|
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 |
| Belgium |
| Bulgaria |
| Denmark |
| Estonia |
| Finland |
| France |
| Germany |
| Hungary |
| Italy |
| Lithuania |
| Norway |
| Poland |
| Spain |
| Sweden |
| United Kingdom |
| Czechia |
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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