IRB Study Number 25-229
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
To determine the safety and tolerability of TUB-030
To determine the maximum tolerated dose (MTD) if observed of TUB-030 as a single agent in patients with advanced solid tumors
Secondary Objectives
To determine the doses for optimization (IDO) of TUB-030
To characterize the PK profiles of TUB-030 (conjugated antibody), total antibody (mAb) and free payload (exatecan)
To evaluate the immunogenicity of TUB-030 and explore association with exposure of TUB-030
To evaluate preliminary clinical activity and safety of TUB-030
Inclusion Criteria
Male or non-pregnant, non-breastfeeding female aged 18 years or older at the date of consent.
Adequate hematologic function as indicated by:
Platelet count ≥100,000/mm3 (no transfusion or growth factors e.g. eltrombopag, romiplostim, or IL-11 within 2 weeks before first dose)
Hemoglobin ≥8.0 g/dL (no transfusion or growth factors e.g. erythropoietin [EPO], darbepoetin within 2 weeks 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 2 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 by: a total bilirubin level ≤1.5 × ULN, an aspartate aminotransferase (AST) level ≤2.5 × ULN, and an alanine aminotransferase (ALT) level ≤2.5 × ULN, 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
Adequate renal function defined by glomerular filtration rate ≥60 mL/min (according to the Chronic Kidney Disease Epidemiology Collaboration, CKD-EPI, formula).
Patients who received anti-cancer treatment including chemotherapy, biological therapy (e.g., antibodies), endocrine therapy, PARP inhibitor, or other oral or investigational drugs must have had their last dose at least 4 weeks (6 weeks for nitrosourea, mitomycin-C) or 5 half-lives, whichever is shorter, before C1D1 treatment with TUB-030.
AEs related to prior therapy, radiotherapy or surgical procedures must resolve to ≤grade 1, exceptions to this include hyperpigmentation, discoloration (including vitiligo) of the skin and nails, stable immune-related toxicity such as hypothyroidism on hormone replacement, stable immune-related toxicities requiring up to 10 mg daily prednisone (or equivalent), or chronic peripheral sensory neuropathy grade ≤ 2.
For patients with known brain metastases evidence of clinically stable disease post radiation therapy is required prior to enrollment. The final dose of stereotactic radiation must have been administered ≥ 7 days, or the final dose of whole brain radiation must have been administered ≥ 14 days prior to C1D1.
For patients who underwent radiotherapy (≥ 30% of the bone marrow or wide field) to sites outside the brain, the final dose of radiation must have been administered ≥ 28 days prior to C1D1. For patients who underwent palliative radiotherapy (≤ 30% of the bone marrow or wide field) the final dose of radiation must have been administered ≥14 days prior to C1D1.
Radiologically measurable disease by RECIST v1.1, 4 weeks before C1D1, that can include a lesion in an irradiated field that shows progression according to RECIST v1.1 after irradiation; see Appendix D.
Eastern Cooperative Oncology Group (ECOG) 0-1; see Appendix A.
Have a life expectancy of >12 weeks for disease-related mortality, as evaluated by the INV.
Informed consent and tissue availability
In the opinion of the INV, the patient must be able and willing to understand and give signed informed consent, for compliance with the requirements and restrictions listed in the ICF and this protocol.
Patients must have adequate archival tissue available (1 formalin-fixed and paraffin-embedded [FFPE] block, or 20 unstained freshly cut sections (minimum of 6) from the most recently available tumor sample) or agree to undergo a fresh biopsy. Patients must sign an archival tissue release form for research purposes and determination of biomarker (e.g., 5T4) expression.
A requirement for a fresh biopsy may be waived at the Sponsor’s discretion at dose levels < 1.0mg/kg.
A fresh pre-treatment biopsy is strongly recommended for HNSCC and soft tissue sarcoma patients.
For NSCLC only, a specimen from a fine needle biopsy is acceptable if at least 6 freshly cut sections can be submitted.
Sexual activity
- 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 5 half-lives and 6 months add-on 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 repeated with available results before the administration of treatment cycles according to Table 18 and at EoT. 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-030 based on the PK study in humanized FcRn mice (Tg32 model) is 73.4 hours for intact ADC. Based on allometric scaling, in human a half-life of 10.9 days is predicted for the intact ADC.
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 anti-hormonal 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.
- Males must use an effective barrier method of contraception without interruption if the patient is sexually active with an WOCBP until the end of exposure, 5 half-lives plus 6 months add-on after the end of treatment. In addition, their female partners who are WOCBP should agree to use 1 highly effective barrier method of contraception at the same time. Male patients should refrain from donating sperm during study participation and for 6 months after the last dose of the study drug.
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.
- Human immunodeficiency virus (HIV)-infected patients must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease defined as:
A. Patients on ART must have a CD4+ T-cell count >350 cells/mm3 at time of screening.
B. Patients on ART must have achieved and maintained virologic suppression, defined as confirmed HIV ribonucleic acid (RNA) level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks before screening.
C. Patients on ART must have been on stable regimen, without changes in drugs or dose modification, for at least 4 weeks before C1D1.
7.1.1.1 Inclusion Criteria For Patients in Phase I Dose Escalation
Patients with locally advanced or metastatic disease that are intolerant or refractory to standard therapy or for which no standard therapy is judged appropriate by the INV.
Histologically confirmed diagnosis of tumors likely to express 5T4 including: HNSCC, NSCLC, SCLC, pleural mesothelioma, triple negative breast cancer (TNBC) and HR+ breast cancer, esophageal cancer, gastric cancer, pancreatic adenocarcinoma, CRC, bladder cancer, prostate cancer, cervical cancer, osteosarcoma, chondrosarcoma, or soft tissue sarcomas expressing.
7.1.1.2 Inclusion Criteria For Patients in Phase I Backfill Cohorts and Phase 2a Dose Optimization
Inclusion Criteria For HNSCC
Unresectable or locally recurrent or metastatic HNSCC with primary tumor site arising from the oral cavity, oropharynx, hypopharynx, and larynx independent of HPV status (high-risk HPV-specific testing or by p16 IHC) and PD-L1 status (both HPV and PD-L1 status must be known and documented).
Must have progressed on or be refractory or intolerant to at least 1 prior line of therapy with SoC e.g. platinum-based therapy and either anti-epidermal growth factor receptor (EGFR) agent or immunotherapy, if indicated, and no standard therapy is judged appropriate by the INV.
Patient was previously treated with a maximum of 3 prior lines of therapy in the advanced/metastatic setting.
Inclusion Criteria For NSCLC
Histologically-confirmed NSCLC of (i) squamous cell carcinoma of the lung or, (ii) adenocarcinoma of the lung, or iii) mixed adeno-squamous subtypes.
Must have progressed on or be refractory or intolerant to at least 2 prior lines of therapy with SoC, e.g., platinum-based doublet, taxanes alone or in combination with antiangiogenic agent, pemetrexed, and/or checkpoint inhibitors (±bevacizumab), if indicated, and no standard therapy is judged appropriate by the INV.
Patient was previously treated with a maximum of 3 prior lines of therapy in the advanced/metastatic setting. Patients with tumors harboring actionable genomic alterations (e.g., mutations in EGFR, ROS1, or other genes with approved targeted therapies) are eligible if they have progressed on prior approved targeted therapy and have progressed on or been refractory or intolerant to either a platinum containing chemotherapy regimen or a regimen including a checkpoint inhibitor.
Alternative Indications of Interest for Backfill and Dose Optimization
Inclusion Criteria for TNBC
- Histologically or cytologically documented, locally recurrent, inoperable TNBC, or metastatic TNBC. TNBC is defined as:
Negative for estrogen receptor (ER) with <1% of tumor cells positive for ER on IHC.
Negative for progesterone receptor with <1% of tumor cells positive for progesterone receptor on IHC.
Negative for HER2 with 0 or 1+ intensity on IHC or 2+ intensity on IHC and negative by ISH per the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) HER2 guideline.
- Must have progressed on or be refractory or intolerant to at least 3 prior lines of therapy with SoC, e.g., taxanes, anthracyclines, cyclophosphamide, platinum-compounds and if PD(L)1-positive, patients must have received a combination of chemotherapy and/or checkpoint inhibitors if indicated (atezolizumab or pembrolizumab), and no standard therapy is judged appropriate by the INV
If germline BReast CAncer gene (BRCA) 1 or 2 mutation is present, patients must have received SoC therapies including a PARPi, unless not a candidate for these therapies. Patients previously treated with sacituzumab govitecan are accepted in this study.
- Patient was previously treated with a maximum of 4 prior lines of therapy in the advanced/metastatic setting.
Inclusion Criteria for CRC
Unresectable, recurrent or metastatic microsatellite stability (MSS; excluded are high microsatellite instability [MSI]) colorectal adenocarcinoma.
Must have progressed on or be intolerant to at least 2 prior lines of SoC, that must include all of the following agents: Fluoropyrimidine Irinotecan Platinum agents (e.g. oxaliplatin) An anti-EGFR agent, if clinically indicated An anti-vascular endothelial growth factor (VEGF) agent, if clinically indicated (e.g. bevacizumab) A BRAF inhibitor, if clinically indicated (e.g. BRAF V600E positive) Prior anti-HER2 treatment in HER2+tumors Prior KRAS-G12C inhibitor if KRAS G12C+
Patient was previously treated with a maximum of 4 prior lines of therapy in the advanced/metastatic setting, and no standard therapy is judged appropriate by the INV
Exclusion Criteria
Medical conditions
Patient is pregnant, lactating or breastfeeding or has a positive serum pregnancy test during the screening period.
History of hypersensitivity to exatecan or excipients of the TUB-030 formulation.
Note: The excipients of TUB-030 are listed in Section 8.2.
Disease that progressed on treatment with an ADC that is formulated with payloads that are either Dxd, exatecan, or SN38; treatment with an ADC with other payloads are allowed.
Prior treatment with any drug or investigational agent targeting 5T4.
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.
Patients with untreated spinal cord compression or cerebrovascular accident/stroke within <6 months of enrollment.
History of progressive multifocal leukoencephalopathy.
Patients with unresolved bowel obstruction, including patients with radiological findings indicating bowel obstruction on diagnostic imaging.
Chronic skin condition that requires systemic therapy.
Surgery within 21 days before signing the ICF, unless the INV judges the patient is recovered at that time.
History of non-infectious ILD/pneumonitis/radiation pneumonitis that required steroid therapy or is suspected of having active ILD/pneumonitis based on imaging and symptoms.
Diagnosis of grade ≥2 fever within 1 week before enrollment. Patients with grade 1 fever may be eligible if in the judgement of the INV the fever is likely due to tumor and not infection.
Active clinically significant corneal disease, or history of clinically significant corneal disease within 12 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 investigational agent.
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 non-malignant 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 (CHF) (New York Heart Association III or IV). Coronary revascularization procedure within 180 days of study entry. Calculated QTc average (using the Fridericia correction calculation) of >470 msec.
Any concurrent anti-cancer chemotherapy, radiotherapy (except for local radiation therapy of lesions that may cause imminent complications), hormonal therapy (except hormonal therapies acting on the hypothalamic-pituitary-gonadal axis i.e. luteinizing hormone-releasing hormone agonist/and agonists or hormone therapy for benign prostate neoplasm/hypertropia). No other anticancer therapy, immunotherapy, or corticosteroid therapy (for cancer) is permitted, other than therapy noted in Section 8.7.
Live attenuated vaccines within 30 days prior to enrollment.
Patients with an active and symptomatic fungal, bacterial, or viral infection (including COVID-19).
Concurrent therapy
- Patients currently receiving (or unable to stop prior to receiving the study intervention TUB-030) prohibited medication, e.g., strong CYP3A4, CYP1A2 inhibitors and strong CYP3A4 substrates (see Section 8.7.1).
7.2.1 Exclusion Criteria For Phase I Backfill Cohorts and Phase 2 Dose Optimization
Exclusion Criteria For HNSCC
- HNSCC arising from paranasal sinus, salivary gland cancer, nasopharyngeal carcinoma.
Exclusion Criteria For NSCLC
- History of a prior pneumonectomy
Note: Other types of surgery including lobectomy, bilobectomy, segmentectomy and wedge resections are allowed
