Study of TUB-040 in Patients With Recurrent or Progressive Uterine Cancer After Chemotherapy and Immune Therapy

Official title

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

Overview

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.

Interventions

• Drug TUB-040 - Dose escalation
  TUB-040 will be administered as an intravenous (IV) solution on day 1 of each treatment cycle.
• Drug TUB-040 - RP2D
  TUB-040 will be administered as an intravenous (IV) solution on day 1 of each treatment cycle. Dose based on the RP2D

Primary outcome measures

• Phase 1: Percentage of Participants Experiencing Treatment-emergent Adverse Events (TEAEs) [Time frame: Up to 3 years]
• Phase 1: Percentage of Participants Experiencing Dose-Limiting Toxicities (DLTs) [Time frame: Up to 3 years]
• Phase 2: Overall Response Rate (ORR) [Time frame: Up to 3 years]

Secondary outcome measures (12)

• Phase 1: Overall Response Rate (ORR) [Time frame: Up to 3 years]
• Phase 1: Duration of Response (DOR) [Time frame: Up to 3 years]
• Phase 1: Progression-Free Survival (PFS) [Time frame: Up to 3 years]
• Phase 1: Disease Control Rate (DCR) [Time frame: Up to 3 years]
• Phase 1: Overall Survival (OS) [Time frame: Up to 3 years]
• Phase 1: Change From Baseline in Fridericia's Corrected QT interval (QTcF) [Time frame: Up to 3 years]
• Phase 1: Pharmacokinetic (PK) parameter: Cmax [Time frame: Up to 3 years]
• Phase 1: Pharmacokinetic (PK) parameter: Tmax [Time frame: Up to 3 years]
• Phase 1: Pharmacokinetic (PK) parameter: AUC [Time frame: Up to 3 years]
• Phase 1: Pharmacokinetic (PK) parameter: t1/2 [Time frame: Up to 3 years]
• Phase1/Phase2: Percentage of Participants Who Develop Anti-TUB-040 Antibodies as appropriate [Time frame: Up to 3 years]
• Phase 2: Durability of Response (DOR) [Time frame: Up to 3 years]

Eligibility criteria

Inclusion criteria

• Histologically confirmed advanced recurrent or progressive serous or endometroid endometrial cancer.

Note: Mixed histologies are allowed if the dominant subtype is serous or endometroid.

• Pathological report with results of institutional MMR and/or MSI testing.
• 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 (PD-L1) or programmed death-1 (PD-1) inhibitor therapy (separately or in combination) Note: Induction plus maintenance is considered as 1 line of therapy. Hormonal therapy without chemotherapy will not be considered a separate line of therapy

For dose escalation cohorts only:

The requirement for prior treatment with a PD-1 or PD-L1 inhibitor is waived for patients enrolled in countries where treatment with these agents does not have regulatory approval for first line treatment after discussion with and approval from the Sponsor's medical monitor.

• Radiographic progression on or after the most recent line of anticancer therapy.
• Female aged ≥ 18 years at the time of consent.
• Disease not amenable to curative intent treatment.
• 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.
• ECOG performance status of 0 or 1.
• Life expectancy > 12 weeks for disease-related mortality as evaluated by the INV.
• Willing to sign an archival tissue release form for research purposes and determination of biomarker (eg, NaPi2b) expression. An adequate tumor tissue sample, either a formalin-fixed, paraffin-embedded (FFPE) 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
• Willing to undergo a noncontrast high-resolution computed tomography (HRCT) scan of the thorax and pulmonary function testing at screening.
• 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):

• Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase and alanine aminotransferase (ALT)/serum glutamic pyruvate transaminase ≤ 3.0 × the upper limit of normal (ULN)
• 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.
• Estimated glomerular filtration rate (eGFR) > 50 mL/min calculated using the Chronic Kidney Disease Epidemiology Collaboration formula (Appendix B)
• 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
• Hemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count ≥ 1500/mm3
• Platelet count ≥ 100,000/mm3
• 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
• 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).
• 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).
• 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.
• Ability to understand, give written informed consent, comply with all study-related procedures, medication use, and assessments.
• No history of noncompliance with medical regimens or considered, in the opinion of the INV, to be potentially unreliable and/or uncooperative.
• Willing to sign and date the ICF

Exclusion criteria

• Unresolved bowel obstruction, including radiographic findings consistent with bowel obstruction plus clinical signs and symptoms of obstruction such as nausea and/or vomiting.
• Prior thoracocentesis for therapeutic drainage of malignant effusion within 4 weeks prior to initiation of study treatment.
• Paracentesis for therapeutic drainage of malignant effusion within 4 weeks prior to initiation of study treatment.
• Receiving total parenteral nutrition.
• Serum albumin < 2.5 g/dL (patients should not receive IV albumin within 4 weeks prior to testing).
• 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.
• Pregnant, lactating, or breastfeeding.
• History of hypersensitivity to exatecan or excipients of the TUB-040 formulation.
• Prior treatment with an ADC-containing Topo-1 inhibitor payload. ADCs with other payloads are allowed (eg, monomethyl auristatin E, monomethyl auristatin F).
• Discontinuation of the most recent systemic anticancer therapy due to hematologic toxicity.
• 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.
• Chemotherapy or other anticancer therapy within 4 weeks or 5 half-lives (whichever is shorter) prior to initiation of study treatment.
• 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.
• 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.

• Active ILD/pneumonitis or history of noninfectious ILD/pneumonitis/radiation pneumonitis that required steroid treatment.
• Oxygen saturation of < 93% on room air at rest
• 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.
• History of nephrotic syndrome or proteinuria Grade ≥ 2.
• Active corneal disease, or history of corneal disease within 4 months prior to enrollment.
• 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.
• 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.
• 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).
• Any concurrent anticancer chemotherapy, radiotherapy (palliative radiation may be permitted after approval by the sponsor in accordance with protocol), hormonal therapy, immunotherapy, corticosteroid therapy other than that permitted in protocol), or any other prohibited medications as listed in protocol.
• Live vaccines within 30 days prior to study enrollment.
• Concomitant use of strong inhibitors or strong inducers of cytochrome P450 (CYP)3A4.
• 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.
• Positive for hepatitis B surface antigen (HbsAg) or hepatitis B (HBV) DNA.
• Active acute or chronic infection.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 4 centers

• START Los Angeles — Los Angeles
• START New Jersey — East Brunswick
• START New York-Long Island — Lake Success
• START Mountain Region, LLC — West Valley City

Identifiers

NCT: NCT07743541 · NAPISTAR 1-03

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗