Study of TUB-040 Given With Standard Ovarian Cancer Drugs in Patients With Fast-growing Ovarian Cancer

Inclusion criteria

• Female ≥ 18 years of age at the time of the first screening visit
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1
• Histologically confirmed advanced high-grade serous or endometrioid epithelial ovarian, fallopian tube or primary peritoneal cancer.
• Have platinum-sensitive ovarian cancer (PSOC) defined as: Patients who had recurrences (radiologically confirmed) to platinum-based therapy and have responded to the last platinum therapy received before study entry and did not progress within 6 months (182 days) of the date of the last dose of platinum-based systemic treatment.
• Radiologically measurable disease in at least 1 lesion by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1, that can include a lesion in an irradiated field and that shows progression according to RECIST v1.1
• Patients must have progressed radiographically on or after their most recent line of anticancer therapy
• Adequate hematologic function as indicated by:

• Platelet counts ≥100,000/mm3 (no transfusion or growth factors, e.g., eltrombopag, romiplostim, or IL-11 within 4 weeks before first dose)
• Hemoglobin ≥9.0 g/dL (no transfusion or growth factors e.g. erythropoietin (EPO), darbepoetin within 4 weeks before first dose or long-acting white blood cell growth factors within 20 days before first dose)
• Absolute neutrophil count (ANC) ≥1500/μL (no growth factors, e.g., granulocyte colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF) within 4 weeks before first dose)
• International normalized ratio (INR) ≤1.5 and activated partial thromboplastin time (aPTT) ≤1.5 × upper limit of normal (ULN) in the absence of anticoagulation therapy. If patients are on anticoagulation therapy with a specific INR goal, INR should be within the therapeutic range for the medical indication.
• Adequate hepatic function defined as total bilirubin level ≤1.5 × ULN, an aspartate aminotransferase (AST) level ≤2.5 × ULN, and an alanine aminotransferase (ALT) level ≤2.5 × ULN

• For documented Gilbert's Syndrome, a total bilirubin <3 × ULN is accepted
• For patients with liver metastases, AST and ALT <5 × ULN is accepted
• Alkaline phosphatase < 2.5 x ULN, except if there is an alternative explanation for ALP elevation rather than hepatic failure, such as the presence of bone metastasis
• Adequate renal function defined by glomerular filtration rate ≥60 mL/min (according to the Chronic Kidney Disease Epidemiology Collaboration, CKD-EPI, formula [Appendix B]).
• Patients must be willing to sign an archival tissue release form for research purposes and determination of biomarker (e.g., NaPi2b) expression. The patient must have an adequate tumor tissue sample available for biomarker assessment by the central laboratory. Mandatory is either a tissue (FFPE) block or a minimum of 6 freshly cut unstained sections based on the most recently available tumor sample. If no archival specimens are available, a new biopsy must be performed. For patients in which a fresh biopsy poses unacceptable clinical risk in the judgment of the treating investigator, enrollment may be considered on a case-by-case basis only after discussion with the Sponsor Medical Monitor.
• Resolution of all acute toxic effects of prior therapy or surgical procedures to Grade ≤1 including peripheral neuropathy (except alopecia, hyperpigmentation, or discoloration (incl. vitiligo) of the skin and nails, stable immune-related toxicity such as hypothyroidism on hormone) replacement, corticosteroid treatment on ≤10 mg daily prednisone (or equivalent)
• Patients with previous systemic topoisomerase 1 inhibitor treatment (e.g., Topotecan) or patients that are previously treated with ADCs are allowed (except for ADCs with a topoisomerase 1 inhibitor, such as SN38 or other camptothecin derivatives as payload or any ADC targeting NaPi2b)
• Completed washout of prior therapy:

• Systemic anti-neoplastic therapy: five half-lives or 4 weeks, whichever is shorter prior to first dose of study drug. Hormonal therapy is not considered anti-neoplastic therapy.
• Radiotherapy: last dose ≥ 2 weeks from first dose of study drug
• Completed major surgery at least 4 weeks prior from first dose of study drug and recovered from side effects to Grade ≤1.
• Viral infections:

• Patients who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B (HBV) anti-viral therapy for at least 4 weeks and have undetectable HBV viral load Note: Patients should remain on anti-viral therapy throughout study intervention and follow local guidelines for HBV anti-viral therapy post-completion of study intervention.
• Patients with history of hepatitis C viral (HCV) infection are eligible if HCV viral load is undetectable at screening. Note: Patients must have completed curative anti-viral therapy at least 4 weeks before enrollment
• Women of childbearing potential (WOCBP) who are sexually active with a non-sterilized partner must use at least 1 highly effective method of contraception (with a failure rate of ≤1% per year) from the time of screening and must agree to continue using such precautions until the end of exposure, plus at minimum 5 half-lives and 6 months after last dose of either TUB-040, carboplatin, or bevacizumab, whichever is later, in the case of patients of childbearing potential. Abstinence is acceptable only when this is in line with the preferred and usual lifestyle of the patient for the duration of the study treatment and the above-referred period after the end of the exposure. Periodic abstinence (e.g. calendar ovulation, symptom-thermal, post-ovulation methods), the rhythm method, and the withdrawal method are not acceptable methods of contraception.

Note: A pregnancy test (urine or serum test or per institutional guideline) 72 hours before enrollment is required in WOCBP. Within 72 hours before enrollment, if a positive urine pregnancy test result is confirmed using a serum test, then the patient should not be enrolled into the study. Pregnancy tests (urine or serum test per institutional guideline) should be performed within 72h and resulted prior to the administration of any study treatment, at End of Treatment, and during Follow-Up as mandated by the Schedule of Assessments. In Follow-Up, this is continued monthly for 5-half-lives + 6 months after the last dose of any drug under study, at minimum. Women who have undergone a hysterectomy and/or bilateral salpingo-oophorectomy are exempted from testing.

• Patients must agree to continue a highly effective contraceptive method, refrain from egg cell donation and breastfeeding while on study treatment and for 5 half-lives plus 6 months after the last dose of study treatment.

Note: The half-life of TUB-040 is approximately 6 days.

• Female patients will be considered post-menopausal if they have undergone bilateral salpingectomy, and/or bilateral oophorectomy, and/or hysterectomy or have been amenorrheic for 12 months without an alternative medical cause (treatment with antihormonal therapies is considered an alternative medical cause). The following age specific requirements apply:

• Women <50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all hormonal replacement therapy and/or if they have luteinizing hormone and follicle stimulating hormone levels in the post-menopausal range for the institution.
• Women ≥50 years of age will be considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all hormonal replacement therapy or had radiation-induced menopause with most recent menses >1 year ago or had chemotherapy-induced menopause with most recent menses >1 year ago.
• In the opinion of the INV, the patient must be able to understand, must be willing to sign informed consent form (ICF) and comply with all study-related procedures, medication use, and evaluations.
• Patients must have 1-2 prior lines of systemic platinum therapy and have not progressed within 182 days after the date of the last dose of platinum.

Notes:

I. Neoadjuvant ± adjuvant is considered as one line of therapy.

II. Maintenance therapy (e.g., BEV, poly adenosine diphosphate-ribose polymerase inhibitors (PARPi)) does not count as a line of therapy.

III. Prior treatment may include BEV

• Prior treatment with PARPi is required (for patients who were previously documented to be HRD positive or have a germline or somatic BRCA 1/2 mutation), if PARPi therapy was locally approved at the time of testing.

Exclusion criteria

• Patients with clear-cell, mucinous histology, mixed histology with mucinous component, sarcoma, sarcomatous component, or low-grade ovarian cancer
• Patients with platinum refractory ovarian cancer (OC) (Platinum refractory is defined as disease that has not responded to a primary platinum-based regimen or progressed within 30 days after primary platinum-based therapy) or platinum resistant ovarian cancer
• Patient pregnant, lactating or breastfeeding or having a positive serum pregnancy test during the screening period
• Previous systemic topoisomerase-1 inhibitor treatment (except Topotecan)
• History of hypersensitivity to monoclonal antibodies, exatecan or excipients of the TUB-040 formulation.

Note: The excipients of TUB-040 are listed in the IB.

• Patients with unresolved malignant bowel obstruction (including patients with radiological findings indicating possible bowel obstruction on CT scans), history of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess or Patients on total parenteral nutrition (TPN)
• Prior thoracocentesis for therapeutic drainage of malignant effusion < 4 weeks from trial inclusion and repeated paracentesis for therapeutic drainage of malignant effusion < 4 weeks before trial inclusion
• Prior radiotherapy to the pelvis or abdomen (Dose Escalation phase only)
• Patients with serum albumin level <2,5 g/dL (subjects should not have received IV albumin within 4 weeks of the test)
• Participation in interventional clinical studies either concurrently or within the previous 28 days or within 5 half-lives (whichever is shorter) of any investigational pharmacologic agents before study treatment
• Patients with untreated spinal cord compression or cerebrovascular accident/stroke within <6 months of enrollment
• Major surgery within 21 days prior to signing the ICF, unless the patient is recovered at that time
• History of non-infectious ILD/pneumonitis/radiation pneumonitis that required steroids or has current ILD/pneumonitis
• Documented cardiac comorbidities: Corrected QT interval > 470 msec on the screening ECG, unstable or uncontrolled pectoral angina, myocardial infarction during the last 6 months, valvular heart disease that requires treatment, uncontrollable hypertension (≥Grade 3), uncontrollable arrhythmias, acute myocarditis, or congestive heart failure (CHF) (New York Heart Association III or IV) or severe aortic stenosis
• Active, uncontrolled or severe impairment of the urogenital, renal, hepatobiliary (including liver cirrhosis), 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
• Demyelinating diseases: History of multiple sclerosis or of progressive multifocal leukoencephalopathy
• 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.
• Any concurrent anti-cancer chemotherapy, radiotherapy (except for local radiation therapy of lesions that may cause imminent complications), hormonal therapy, immunotherapy, or corticosteroid therapy, other than that permitted in Section 8.8.
• Live vaccines within 30 days prior to study entry or any known unresolved and active bacterial, viral (e.g. Hep B, Hep C, Varicella or CMV), fungal, mycobacterial, or other infection at screening
• History of hypersensitivity to Carbo and risk of further cumulative toxicity with additional platinum, including but not limited to myelosuppression, with febrile neutropenia, Grade 4 hematotoxicity, neuropathy Grade ≥2, renal insufficiency during prior platinum-based therapy
• Non-healing wounds, ulcers, or bone fractures
• History of posterior reversible encephalopathy syndrome
• Recent history of hemoptysis of ≥1/2 teaspoon of red blood within 4 weeks before first study treatment,
• History of Grade 4 thromboembolic events
• Hypertension ≥ Grade 3 that is not controlled with medical management
• Clinically significant proteinuria: urine-protein (UPC) ratio ≥ 1.0 or urine dipstick result ≥ 2+; patients with UPC ratio ≥ 1.0 or ≥ 2+ proteinuria should undergo 24-hour urine collection and must show result < 1 gram of protein in 24-hour period.
• Any patient who is required to take strong CYP3A4 inhibitors or inducers (see also Prohibited Medication and Guidance for Potential Use section).

• Note: If it is clinically acceptable to replace such medication with a different medication which is not a strong CYP3A4 inhibitor or inducer, then the patient may be eligible.