A Multicenter Phase 1/2 Study to Investigate Safety, Tolerability, Pharmacokinetics, and Efficacy of the NaPi2B Antibody-Drug Conjugate TUB-040 in Patients With Recurrent or Progressive Uterine Endometrial Cancer After Platinum-Based Chemotherapy and Immune Checkpoint Inhibitor Therapy

Study Identifier:
NAPISTAR 1-03
CT.gov Identifier:
NCT07743541
EudraCT Identifier:
202652687222
EU Trial (CTIS) Number:
N/A
Study Contact Information:
N/A
Will Be Recruiting

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Study Summary

The goal of this clinical study is to learn more about the study drug TUB-040, safety, tolerability, pharmacokinetics (PK), and effectiveness in treating patients with recurrent or progressive uterine endometrial cancer after platinum-based chemotherapy and immune checkpoint inhibitor therapy.

The primary objectives of Phase 1 of this study are to determine the safety and tolerability of TUB-040 and determine the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D).

The primary objective of Phase 2 of this study is to evaluate the efficacy of TUB-040 monotherapy at the RP2D in endometrial cancer.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Endometrial
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I/II
Sex
Female
Age
18+ years
Study Drug
Drug: EXPERIMENTAL: Phase 1: Dose Escalation of TUB-040
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Drug: Participants will receive escalating doses of TUB-040 to determine recommended Phase 2 dose (RP2D).
Drug: Drug: TUB-040 - Dose escalation
Drug: TUB-040 will be administered as an intravenous (IV) solution on day 1 of each treatment cycle.
Drug: EXPERIMENTAL: Phase 2: Monotherapy of TUB-040
Drug: Participants in Phase 2 will receive the recommended dose of TUB-040 monotherapy determined in Phase
Drug: Drug: TUB-040 - RP2D
Drug: TUB-040 will be administered as an intravenous (IV) solution on day 1 of each treatment cycle. Dose based on the RP2D
Study Status
Indicates the current recruitment status or the expanded access status
Will Be Recruiting

Requirements information
Inclusion criteria
  • 1. Histologically confirmed advanced recurrent or progressive serous or endometroid endometrial cancer.
  • Note: Mixed histologies are allowed if the dominant subtype is serous or endometroid.
  • 2. Pathological report with results of institutional MMR and/or MSI testing.
  • 3. Received at least 1 but no more than 3 prior lines of anticancer therapy:
  • a. Must have received at least 1 line of platinum-based therapy and 1 line of programmed death ligand-1 inhibitor therapy (separately or in combination) Note: Patients who were unable to receive immunotherapy for a medical reason (eg, autoimmune disease) may be enrolled after discussion with and approval from the sponsor's medical monitor. Induction plus maintenance is considered as 1 line of therapy. Hormonal therapy without chemotherapy will not be considered a separate line of therapy
  • 4. Radiographic progression on or after the most recent line of anticancer therapy.
  • 5. Female aged ≥ 18 years at the time of consent.
  • 6. Disease not amenable to curative intent treatment.
  • 7. Radiologically measurable disease by RECIST v1.1, which can include a lesion in an irradiated field that showed progression by RECIST v1.1 after irradiation.
  • 8. ECOG performance status of 0 or 1.
  • 9. Life expectancy > 12 weeks for disease-related mortality as evaluated by the INV.
  • 10. Willing to sign an archival tissue release form for research purposes and determination of biomarker (eg, NaPi2b) expression. An adequate tumor tissue sample, either formalin-fixed, paraffin-embedded tissue block or a minimum of 6 freshly cut, unstained sections of the most recently available tumor sample, is mandatory for biomarker assessment by the central pathology laboratory. If no archival specimens are available, a newly acquired biopsy specimen must be provided.
  • 11. Willing to undergo a noncontrast high-resolution computed tomography (HRCT) scan of the thorax and pulmonary function testing at screening.
  • 12. Adequate organ function as defined by all of the following criteria (parameters must be met without growth factor or transfusion support within 4 weeks prior to enrollment):
  • 1. Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase and alanine aminotransferase (ALT)/serum glutamic pyruvate transaminase ≤ 3.0 × the upper limit of normal (ULN)
  • 2. Total serum bilirubin ≤ 1.5 × ULN (CTCAE Grade ≤ 1) unless secondary to Gilbert's syndrome. Patients with Gilbert's syndrome may be included if their unconjugated bilirubin is ≤ 3 × ULN.
  • 3. Estimated glomerular filtration rate (eGFR) > 50 mL/min calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (Appendix B)
  • 4. Alkaline phosphatase (ALP) < 2.5 × ULN, except if there is an alternative explanation for ALP elevation other than hepatic failure, such as the presence of bone metastasis
  • 5. Hemoglobin ≥ 9.0 g/dL
  • 6. Absolute neutrophil count ≥ 1500/mm3
  • 7. Platelet count ≥ 100,000/mm3
  • 8. International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN in the absence of anticoagulation therapy. If patients are on anticoagulation therapy, INR should be within the therapeutic range for the medical indication
  • 13. Resolution of all AEs from prior therapy or surgical procedures to Grade ≤ 1 or to baseline (exceptions included alopecia, hyperpigmentation or discoloration of the skin and nails [including vitiligo], stable immune-related toxicity such as hypothyroidism for patients on hormone replacement or corticosteroid treatment with prednisone, or equivalent, of ≤ 10 mg daily, and Grade 2 peripheral sensory neuropathy after prior treatment with taxane or other anticancer therapy).
  • 14. Women of childbearing potential (WOCP) must have a negative serum pregnancy test during screening and be neither breastfeeding or intending to become pregnant during study participation. A female will be considered to be of childbearing potential following menarche unless they have undergone permanent sterilization (ie, hysterectomy, bilateral salpingectomy, and bilateral oophorectomy) or are postmenopausal. Postmenopausal is defined as at least 12 months without menses with no other medical reason (eg, chemical menopause due to anticancer treatment).
  • 15. For WOCP, agreement must be provided to use a medically approved, highly effective contraceptive method from the time of screening throughout the study and for 6 months after the last administration of study treatment. Refer to Section 5.6 for acceptable methods of contraception.
  • 16. Ability to understand, give written informed consent, comply with all study-related procedures, medication use, and assessments.
  • 17. No history of noncompliance with medical regimens or considered, in the opinion of the INV, to be potentially unreliable and/or uncooperative.
  • 18. Willing to sign and date the ICF
Exclusion criteria
  • 1. Unresolved bowel obstruction, including radiographic findings consistent with bowel obstruction plus clinical signs and symptoms of obstruction such as nausea and/or vomiting.
  • 2. Prior thoracocentesis for therapeutic drainage of malignant effusion within 4 weeks prior to initiation of study treatment.
  • 3. Paracentesis for therapeutic drainage of malignant effusion within 4 weeks prior to initiation of study treatment.
  • 4. Receiving total parenteral nutrition.
  • 5. Serum albumin < 2.5 g/dL (patients should not receive IV albumin within 4 weeks prior to testing).
  • 6. Known active central nervous system metastases and/or carcinomatous meningitis. Note: Previously treated brain metastases allowed if follow-up brain imaging after CNS directed therapy shows no evidence of progression, and they have been off steroids for > 4 weeks prior to first dose.
  • 7. Pregnant, lactating, or breastfeeding.
  • 8. History of hypersensitivity to exatecan or excipients of the TUB-040 formulation.
  • 9. Prior treatment with an ADC-containing Topo-1 inhibitor payload. ADCs with other payloads are allowed (eg, monomethyl auristatin E, monomethyl auristatin F).
  • 10. Discontinuation of the most recent systemic anticancer therapy due to hematologic toxicity.
  • 11. Participation in any interventional clinical studies either concurrently or within 28 days or 5 half-lives (whichever is shorter) prior to enrollment of any investigational pharmacologic agent, imaging materials, including dyes, investigational surgical techniques, or devices.
  • 12. Chemotherapy or other anticancer therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to initiation of study treatment.
  • 13. Radiotherapy < 2 weeks prior to enrollment. Patients with wide-field radiotherapy (> 30% of marrow-bearing bone) must not have had treatment within 4 weeks prior to initiation of study treatment.
  • 14. Major surgery within 21 days prior to signing ICF unless the patient has recovered at that time.
  • Note: Major surgery involves opening of a body cavity such as the thorax or abdomen. A lymph node or skin biopsy is not considered major surgery. Minor surgical procedures such as central venous catheter placement, tumor biopsy, and feeding tube placement are not considered major.
  • 15. Active ILD/pneumonitis or history of noninfectious ILD/pneumonitis/radiation pneumonitis that required steroid treatment.
  • 16. Oxygen saturation of < 93% on room air at rest
  • 17. Resting QTcF > 470 msec. If a single QTcF is > 470 msec, the patient may enroll if the mean QTcF from 3 electrocardiograms (ECGs) is < 470 msec.
  • 18. History of nephrotic syndrome or proteinuria Grade ≥ 2.
  • 19. Active corneal disease, or history of corneal disease within 4 months prior to enrollment.
  • 20. Active, uncontrolled or severe impairment of the urogenital, renal, hepatobiliary, cardiovascular, respiratory, gastrointestinal, neurologic, or hematopoietic systems which, in the opinion of the INV, would predispose the patient to the development of complications from the administration of protocol therapy.
  • 21. History of another malignancy with ongoing treatment or not yet free from disease for 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.
  • 22. Documented other concurrent nonmalignant comorbidities such as unstable or uncontrolled pectoral angina, myocardial infarction during the last 6 months, valvular heart disease that requires treatment, acute myocarditis, or congestive heart failure (New York Heart Association III or IV).
  • 23. Any concurrent anticancer chemotherapy, radiotherapy (palliative radiation may be permitted after approval by the sponsor in accordance with Section 5.5.2), hormonal therapy, immunotherapy, corticosteroid therapy other than that permitted in Section 5.5.1), or any other prohibited medications as listed in Table 18.
  • 24. Live vaccines within 30 days prior to study enrollment.
  • 25. Concomitant use of strong inhibitors or strong inducers of cytochrome P450 (CYP)3A4(Table 18).
  • 26. For Phase 1 only: Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure with reduced ejection fraction or severe diastolic dysfunction, potential for torsades de pointes, congenital long QT syndrome.
  • 27. Positive for hepatitis B surface antigen (HbsAg) or hepatitis B (HBV) DNA.
  • 28. Active acute or chronic infection.
  • Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Clinical Study Information for Healthcare Providers

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START New York (Long Island)
Lake Success, NY, United States, 11042
Investigator
Geraldine O'Sullivan Coyne
Status
Will Be Recruiting
Condition(s) Treated at Site
Endometrial
Location
START Los Angeles
Los Angeles, CA, United States, 90025
Investigator
Status
Will Be Recruiting
Condition(s) Treated at Site
Endometrial
Location
START Mountain Region
West Valley City, UT, United States, 84119
Investigator
Justin Call
Status
Will Be Recruiting
Condition(s) Treated at Site
Endometrial
Location
START New Jersey
East Brunswick, NJ, United States, 08816
Investigator
Bruno Fang
Status
Will Be Recruiting
Condition(s) Treated at Site
Endometrial