A first-in-human study to investigate the safety and tolerability of a new antibody-guided drug delivery treatment for patients with therapy resistant ovarian or lung cancer.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Tubulis GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Respiratory Tract Diseases [C08], Diseases [C] - Female Urogenital Diseases and Pregnancy Complications [C13]

Trial duration

6 Sep 2024 → ongoing

Decision date (initial)

2024-08-14

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Tubulis GmbH

External identifiers

EU CT number

2024-511074-80-01

ClinicalTrials.gov

NCT06303505

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Safety, Therapy, Efficacy, Pharmacokinetic

Phase I Dose escalation
• To determine the safety and tolerability of TUB-040
• To determine the maximum tolerated dose (MTD) or the identified dose for optimization (IDO)

Phase IIa: Dose optimization:
• To assess safety of TUB-040
• To assess the preliminary efficacy of TUB-040
• To identify the RP2D for further development of TUB-040

Secondary objectives 5

1. Key secondary Objective: Phase IIa: Dose optimization- To assess additional measures of preliminary efficacy
2. Phase IIa: Dose optimization - To assess additional measures of preliminary efficacy and safety
3. Phase I: Dose Escalation- To assess additional measures of preliminary efficacy and safety of TUB-040
4. Phase I and IIa: To assess the PK profile of TUB-040 (conjugated ADC), total mAb and free exatecan in presence or absence of bevacizumab
5. Phase I and IIa: To assess the potential immunogenicity of TUB-040 in presence or absence of bevacizumab

Conditions and MedDRA coding

Platinum-resistant high-grade ovarian cancer (PROC) or relapsed/refractory adenocarcinoma non-small cell lung cancer (NSCLC)

Regulatory references

Scientific advice from competent authorities

Paul-Ehrlich-Institut, Food And Drug Administration, Medicines And Healthcare Products Regulatory Agency, Ministry Of Health Of Ukraine

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 24

1. Patients with OC (Cohort 1 and 3):Dose Escalation: Histologically confirmed high-grade serous or endometrioid epithelial ovarian, fallopian tube or primary peritoneal cancer. Criterios de inclusión para el CO (cohortes 1 y 3) Escalada de dosis: Las pacientes con CO deben cumplir todos los criterios siguientes: 1. Cáncer peritoneal primario, de las trompas de Falopio o epitelial de ovario seroso o endometrioide, de alto grado, confirmado mediante estudio histológico Note: mixed histologies are not allowed.
2. All patients: In the opinion of the INV, the patient must be able to understand, give their written informed consent, and comply with all study-related procedures, medication use and evaluations.
3. All patients: The patient must not have a history of non-compliance with medical regimens or be considered potentially unreliable and/or uncooperative.
4. Patients with OC (Cohort 1 and 3) Dose Escalation: Have platinum-resistant disease defined as: a) Patients who have only received one line of platinum-based therapy must have received at least three cycles of platinum and then progressed between 30 and 183 days after the date of the last dose of platinum. b) Patients who have received 2 to 5 lines of prior platinum therapy must have progressed during or within 183 days after the date of the last dose of platinum.
5. All patients: The patient must be willing to sign and date the informed consent form (ICF).
6. Patients with OC (Cohort 1 and 3) Dose Escalation: Have received no more than 4 lines of platinum-based therapy and 2 lines of non-platinum-based therapy in platinum resistant disease.
7. Patients with NSCLC (Cohort 2): Histologically confirmed NSCLC of adenocarcinoma subtype, including its mixed histologies
8. Patients with NSCLC (Cohort 2): Have progressed after previous treatment for locally advanced/metastatic disease that includes a platinum-based doublet if indicated* and/or a checkpoint inhibitor if indicated. *Patients who received indicated first-line checkpoint-inhibitor monotherapy are allowed in the study in the US
9. Patients with NSCLC (Cohort 2): Not a candidate for an existing alternative standard therapy, including KRAS G12C, epidermal growth factor receptor (EGFR), ALK, ROS1 fusions, BRAF V600e mutations, RET fusions, MET exon 14 skipping mutations, human epidermal growth factor receptor 2 alterations, and NTRK fusions.
10. All patients: Male or non-pregnant, non-breastfeeding female aged 18 years or older at the date of consent
11. All patients: Disease not amenable to curative intent treatment
12. All patients: Radiologically measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, that can include a lesion in an irradiated field that shows progression according to RECIST v1.1 after irradiation
13. All patients: Patients have exhausted the standard of care treatment (SoC) with expected clinical benefit and are not denied SoC with expected clinical benefit by participating in the trial.
14. All patients: Patients with previous systemic topoisomerase 1 inhibitor treatment ( e.g Topotecan) are allowed in the study
15. All patients: Eastern Cooperative Oncology Group (ECOG) 0-1; see Appendix A of protocol.
16. All patients: Have a life expectancy of more than 12 weeks for disease-related mortality, as evaluated by the INV.
17. All patients: 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 newly acquired biopsy specimen must be taken. 1. . In dose-optimization, tissue samples must be submitted to the central laboratory during (pre)screening for prospective analysis.
18. All patients: Patients must be willing to undergo a non-contrast high-resolution HRCT of the thorax scan and pulmonary function testing (PFT) at screening.
19. All patients: Adequate organ function, as defined by the following criteria assessed during the screening period.(these parameters must be met without growth factor or transfusion support within 2 weeks of the laboratory study):: a) Aspartate aminotransferase / serum glutamic oxaloacetic transaminase (AST/SGOT) and alanine aminotransferase / serum glutamic pyruvate transaminase (ALT/SGPT) ≤ 3.0 x upper limit of normal (ULN). b) Total serum bilirubin ≤ 1.5 x ULN (CTCAE Grade ≤ 1) unless secondary to Gilbert´s syndrome. Patients with Gilbert´s syndrome may be included if their unconjugated bilirubin is ≤ 3 x ULN. c) Creatinine clearance (eGFR) >60 ml/min either measured by 24h urine collection or calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. d) Alkaline phosphatase (ALP) < 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. e) Hemoglobin ≥9.0 g/dL . f) Absolute neutrophil count ≥1500/mm3 . g) Platelet count ≥100,000 mm3 (=100 G/l) . h) 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.
20. All patients: Resolution of all acute toxic effects of prior therapy or surgical procedures to ≤Grade 1 (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], chronic Grade 2 peripheral sensory neuropathy after prior taxane therapy or anticancer treatment such as but not limited to IOs).
21. All patients: Patients of childbearing potential (FCBP) who are sexually active with a non-sterilized partner must use at least one highly effective method of contraception 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 assigned female at birth. Abstinence is acceptable only as true abstinence 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, symptothermal, post-ovulation methods), the rhythm method, and the withdrawal method are not acceptable methods of contraception. Patients must refrain from egg cell donation and breastfeeding while on study treatment and for at least 7 months after the last dose of study treatment.
22. Dose optimization: Patients with OC: 1.Histologically confirmed high-grade serous or endometrioid epithelial ovarian, fallopian tube or primary peritoneal cancer.
23. Dose optimization: Patients with OC: 2.Have platinum-resistant disease defined as: a)Patients who have only received one line of platinum-based therapy must have received at least three cycles of platinum and then progressed between 30 and 183 days after the date of the last dose of platinum. b) Patients who have received 2 to 4 lines of prior platinum therapy must have progressed during or within 183 days after the date of the last dose of platinum
24. Dose optimization: Patients with OC: Have received 1 to 4 lines of prior systemic therapy, including ≥1 prior line of platinum therapy and prior treatment with BEV, intolerance for or contraindication to treatment with BEV, with documented progressive disease or intolerance to the most recent line of therapy. Notes: i.Neoadjuvant ± adjuvant is considered only 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 with BEV, intolerance for or documented contraindication to BEV is required iv.Prior treatment with PARPi is allowed. v.Any ADC targeting Folate Receptor alpha (except if it carries a topoisomerase 1 inhibitor payload) is allowed.

Exclusion criteria 37

1. Patients with OC (Cohort 1 and3) and Phase IIa Dose Optimisation: Patients with low-grade OC or any grade non-serous non-endometrioid OC.
2. All patients: History of hypersensitivity to exatecan or excipients of the TUB-040 formulation.
3. All patients: Progression on an ADC with a topoisomerase 1 inhibitor as a payload. ADCs with other payloads are allowed (e.g., MMAE, MMAF and others).
4. All patients: Patients with spinal cord compression, active central nervous system disease and/or carcinomatous meningitis.
5. All patients: Patients are not allowed to participate in interventional clinical studies either concurrently or within the previous 28 days or within 5 half-lives of any investigational pharmacologic agents or imaging materials, including dyes, investigational surgical techniques, or devices.
6. All patients: Prior radiotherapy < 2 weeks from trial inclusion, except in the case of stereotactic radiation to the brain (for the NSCLC cohort only), in which case the required interval is 7d
7. All patients: Major surgery within 21 days prior to signing the ICF, unless the patient is recovered at that time.
8. All patients: Has a history of non-infectious ILD/pneumonitis/radiation pneumonitis that required steroids or has current ILD/pneumonitis.
9. All patients: Has an oxygen saturation of <93% on room air at rest.
10. All patients: Has a forced vital capacity <60% and diffusing capacity of the lung for carbon monoxide <70%.
11. All patients: Has a QTcF >470 ms
12. Patients with OC (Cohort 1 and 3 and Phase IIa Dose Optimisation): 2.Patients with primary platinum refractory OC.
13. All patients: History of nephrotic syndrome
14. All patients: Active corneal disease, or history of corneal disease within 4 months prior to enrollment.
15. All patients: 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.
16. All patients: 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.
17. All patients: 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).
18. All patients: 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 8.6.
19. All patients: Live vaccines within 30 days prior to study entry.
20. All patients: Patients with acute or chronic infections such as: a) Patients who are HBsAg positive are eligible if they have received HBV anti-viral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. 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. b)Patients with history of 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 prior to enrollment. c) HIV infected patients must be on anti-retroviral therapy (ART) and have a well-controlled HIV infection/disease defined in Section 7.2.3 of the protocol. d) Any other known unresolved and active bacterial, viral, fungal, mycobacterial, or other infection at screening. e) History of severe and recurrent infections per INV’s judgment. f) History of progressive multifocal leukoencephalopathy.
21. Patients with OC (Cohort 1 and 3) and Phase IIa Dose Optimisation: Patients with unresolved malignant bowel obstruction, including patients with radiological findings indicating bowel obstruction on CT scans such as the presence of elevated air-fluid levels.
22. Patients with OC (Cohort 1 and 3) and Phase IIa Dose Optimisation: Prior thoracocentesis for therapeutic drainage of malignant effusion < 2 weeks from trial inclusion (only for dose escalation).
23. Patients with OC (Cohort 1 and 3) and Phase IIa Dose Optimisation: Repeated paracentesis for therapeutic drainage of malignant effusion < 2 weeks before trial inclusion (only for dose escalation)
24. Patients with OC (Cohort 1 and 3) and Phase IIa Dose Optimisation: Patients on total parental nutrition (TPN)
25. Patients with OC (Cohort 1 and 3) and Phase IIa Dose Optimisation: Patients with serum albumin level <2.5 g/dL (subjects should not have received i.v. albumin within 2 weeks of the test)
26. Patients with NSCLC (Cohort 2): Prior pneumectomy.
27. All patients: The patient is pregnant, lactating or breastfeeding or has a positive serum pregnancy test during the screening period.
28. Patients with OC (Cohort 1 and 3) and Phase IIa Dose Optimisation: Patients with any current or prior central nervous system metastases or leptomeningeal disease.
29. Patients with OC (Cohort 3):1. History of bowel obstruction (including sub-occlusive disease) related to underlying disease within 6 months before the start of study treatment.
30. Patients with OC (Cohort 3):2. History of abdominal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess, or evidence of rectosigmoid involvement by pelvic examination, bowel involvement on computed tomography (CT) scan, or clinical symptoms of bowel obstruction.
31. Patients with OC (Cohort 3): 3. Prior radiotherapy to the pelvis or abdomen.
32. Patients with OC (Cohort 3):4. Surgery (including open biopsy) within 4 weeks before starting study therapy (within 24 hours for minor surgical procedures) or anticipated need for major surgery during study treatment.
33. Patients with OC (Cohort 3): 5. Non-healing wound, ulcer, or bone fracture.
34. Patientes with OC (Cohort 3):6. Hemoptysis ≥ 0.5 teaspoon of red blood within 4 weeks before first study treatment.
35. Patients with OC (Cohort 3): 7. History of posterior reversible encephalopathy syndrome (PRES).
36. Patients with OC (Cohort 3):8. Patients with clinically significant proteinuria: urine-protein (UPC) ratio ≥ 1.0 or urine dipstick result ≥ 2+ should undergo 24-hour urine collection. Patients with 24h urine protein > 1g are excluded.
37. Patients with OC (Cohort 3): 9. History of pulmonary embolization or a grade 4 thromboembolic event.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Phase I: Incidence of dose-limiting toxicities (DLTs) at different dose levels
2. Phase I: Incidence and severity of treatment-emergent adverse events (TEAEs)
3. Phase II: Incidence and severity of TEAEs
4. Phase II: Overall response rate (ORR) as assessed by BICR

Secondary endpoints 5

1. Key Secondary: •Duration of response (DoR) as assessed by BICR
2. Phase IIa: Dose optimization: •Progression free survival (PFS), disease control rate (DCR) as assessed by BICR •Overall response rate (ORR), duration of response (DoR), progression free survival (PFS), disease control rate (DCR) as assessed by INV •Overall survival •Incidence of Grade ≥3 lab abnormalities •Incidence of serious adverse events (SAEs)
3. Phase I: Dose Escalation: • Overall response rate (ORR), duration of response (DoR), progression free survival (PFS), and disease control rate (DCR) as assessed by INV • Incidence of Grade ≥3 lab abnormalities • Incidence of serious adverse events (SAEs)
4. Phase I and IIa: •PK parameters of TUB-040, total mAb and free exatecan, including Cmax, Cmin, Tmax, and as far as collected data allow for a calculated estimation of t1/2, and area under the curve (AUC)
5. Phase I and IIa: •Number and percentage of patients developing anti-TUB-040 antibodies, and semiquantitative titer assessments

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Tubulis GmbH

Sponsor organisation

Tubulis GmbH

Address

Am Klopferspitz 19 A, Martinsried Martinsried

City

Planegg

Postcode

82152

Country

Germany

Scientific contact point

Organisation

Tubulis GmbH

Contact name

Mary Ann A. Lumiqued

Public contact point

Organisation

Tubulis GmbH

Contact name

Mary Ann A. Lumiqued

Third parties 6

Locations

4 EU/EEA countries · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 59 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

10 submissions — initial application plus substantial / non-substantial modifications