A Study to Assess Safety, Tolerability and Imaging Characteristics of [68Ga]Ga-DPI-4452 and to Assess Safety, Tolerability, and Efficacy of [177Lu]Lu-DPI-4452 in Participants With Unresectable Locally Advanced or Metastatic Solid Tumors​

Overview

Sponsor-declared trial summary

Key facts

Sponsor

ITM Oncologics GmbH

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

20 Jun 2023 → ongoing

Decision date (initial)

2024-10-09

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

ITM Oncologics GmbH

External identifiers

EU CT number

2023-504254-35-00

EudraCT number

2022-002573-28

WHO UTN

U1111-1289-0392

ClinicalTrials.gov

NCT05706129

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

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

Part A: To evaluate safety and tolerability of a single intravenous (IV) administration of [68Ga]Ga-DPI-4452 for each tumor type.
Part B: To determine the RP2D of [177Lu]Lu DPI 4452 for each tumor type.
Part C: To evaluate the preliminary antitumor activity of [177Lu]Lu DPI-4452 for each tumor type.
Part D: To assess the diagnostic concordance between [68Ga]Ga-DPI-4452 PET/CT and the histopathology results of the IDRM.
Part E: To assess [68Ga]Ga-DPI-4452 uptake in each tumor type.

Secondary objectives 11

1. 1_Part A: [68Ga]Ga-DPI-4452: Assess PK, biodistribution, and dosimetry and establish the optimal imaging procedure for determining location and burden of positive lesions on imaging
2. 2_Part B: Evaluate the preliminary antitumor activity of [177Lu]Lu-DPI-4452
3. 3_Part B: Assess imaging characteristics of [68Ga]Ga-DPI-4452
4. 4_Parts A, B, C: Assess concordance between [68Ga]Ga-DPI-4452 PET imaging of tumor lesions versus conventional imaging
5. 5_Parts B, C: [177Lu]Lu DPI 4452: characterize safety and tolerability, assess PK, biodistribution, and dosimetry, and assess targeting properties and TBR
6. 6_Parts B, C: Evaluate safety and tolerability of a single IV administration of [68Ga]Ga-DPI-4452
7. 7_Parts B, C: Assess concordance between [68Ga]Ga-DPI-4452 and [177Lu]Lu-DPI- 4452 biodistribution and [68Ga]Ga-DPI-4452 uptake and CA IX expression by IHC (as H-score) in tumor biopsy/cytological samples on a per patient basis and by tumor type
8. 8_Part D: To assess diagnostic accuracy of [68Ga]Ga-DPI-4452 PET/CT in patients with IDRM.
9. 9_Part D: To evaluate safety and tolerability of [68Ga]Ga-DPI4452.
10. 10_Part E: To assess concordance between [68Ga]Ga-DPI-4452 PET imaging of tumor lesions versus conventional imaging (CT/ MRI) on a per patient basis and by tumor type.
11. 11_Part E: To evaluate safety and tolerability of [68Ga]Ga-DPI4452.

Conditions and MedDRA coding

Unresectable locally advanced or metastatic solid tumors: • Clear cell renal cell carcinoma (ccRCC) • Pancreatic ductal adenocarcinoma (PDAC) • Colorectal Cancer (CRC) (Part A) • Urothelial carcinoma (UC) [Part B/C/E] • Indeterminate Renal Mass (IDRM) [part D] • Head and Neck cancer (H&N) [part E] • Triple Negative breast cancer (TNBC) [part E] • Squamous non-mall cell lung cancer (NSCLC) [part E]

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 25

1. 1_Part A: Histologically or cytologically confirmed, unresectable locally advanced or metastatic solid tumors of: -ccRCC; - PDAC; - CRC.
2. 10_Parts B, C: Patient ECOG performance status 0-1
3. 11_Parts B, C: Life expectancy >6 months
4. 12_Parts B, C: Adequate bone marrow reserve and organ function as demonstrated by complete blood count, and biochemistry in blood and urine at Screening
5. 13_Parts B, C: Adequate blood counts: - Hemoglobin ≥9 g/dL - ANC ≥1.5 × 109/L - Platelets ≥100 × 109/L
6. 14_Parts B, C: Adequate hepatic function: - AST, ALT, ALP ≤3.0×ULN (≤5.0×ULN if patient has liver metastases) - Bilirubin ≤1.5 × ULN (a. up to 2.0 × ULN is allowed if the direct bilirubin level is normal, and the elevation is limited to indirect bilirubin b. Up to 5.0 x ULN in case of Gilbert’s Syndrome)
7. 15_Parts B, C: Adequate renal function: - For PDAC, UC patients: eGFR ≥50 mL/min/1.73 m2 (CKD-EPI) - For ccRCC patients: eGFR >40 mL/min/1.73 m2 (CKD-EPI
8. 16_Parts B, C: Adequate coagulation: - International normalization ratio or prothrombin time ≤1.5xULN and no history of major thrombotic or clinically relevant major bleeding event in the past 6 months putting the subject at high risk of bleeding during the study as assessed by the Investigator
9. 2_Part A, E: Measurable disease as per RECIST v1.1
10. 3_Part A: Patient ECOG performance status 0-2
11. 4_Part A: Adequate bone marrow reserve and organ function as demonstrated by complete blood count, and biochemistry in blood and urine at Screening
12. 5_Part A: Adequate blood counts: - Hemoglobin ≥8 g/dL - Absolute neutrophil count (ANC) ≥1.0 × 109/L - Platelets ≥50 × 109/L
13. 6_Part A: Adequate hepatic function: - Aspartate or alanine aminotransferase or alkaline phosphatase (AST, ALT, ALP) ≤ 3.0 × upper limit of normal (ULN) (≤ 5.0 ×ULN if patient has liver metastases) - Bilirubin ≤ 1.5 × ULN (a. up to 2.0 × ULN is allowed if the direct bilirubin level is normal, and the elevation is limited to indirect bilirubin b. Up to 5.0 x ULN in case of Gilbert’s Syndrome)
14. 7_Part A: Adequate renal function: - For PDAC and CRC patients: estimated glomerular filtration rate (eGFR) >50 mL/min/1.73 m² (as determined by the Chronic Kidney Disease - Epidemiology Collaboration - creatinine [CKD-EPIcr] formula) - For ccRCC patients: eGFR > 40 mL/min/1.73 m²(CKD-EPIcr)
15. 8_Parts B, C: Histologically or cytologically confirmed progressive, unresectable locally advanced or metastatic solid tumors of: -ccRCC; - PDAC; -UC.
16. 9_Parts B, C: Measurable disease per RECIST v1.1
17. 17_PART B, C: Presence of at least 1 non-irradiated tumor lesion detected at conventional imaging (CT/MRI) documented after or during the last anticancer therapy and within 64 weeks preceding the planned [177Lu]Lu-DPI-4452 [68Ga]Ga-DPI-4452 administration (for scan dated more than 6 weeks prior to C1D1, the Sponsor should be contacted to assess conventional imaging suitability)
18. 18_Part B and C: ≥75% of the lesions detected by standard imaging (CT scan, MRI) assessed locally by the Investigator (for Part B) or assessed by central reading (Part C) must be positive by [68Ga]GaDPI-4452 PET. Upon agreement between the Sponsor and Investigator, patients with PDAC and patients with UC with <75% lesion positivity may be eligible if their primary tumor or their biggest tumor lesion as detected by standard imaging (CT scan, MRI) is positive by [68 Ga]Ga- DPI-4452 PET as per local assessment.
19. 19_Part B and C: Patients with known central nervous system (CNS) metastasies will be eligible if they are clinically stable, and asymptomatic. Patients must have completed primary CNS therapy more than 4 weeks before treatment start (such as whole brain radiotherapy, stereotactic radiosurgery, or complete surgical resection). Low doses of steroids for the purposes of maintaining neurological integrity (not exceeding of prednisolone 10 mg/day or equivalent) are allowed. For patients with CNS metastasies (or a history of CNS metastasies), baseline and subsequent radiological imaging must include evaluation of the brain (MRI preferred or CT with contrast).
20. 20_Part D: Patients with Imaging evidence of a single indeterminate renal mass of ≤ 7 cm in largest diameter (tumor stage cT1) on any conventional diagnostic imaging technique, suspicious for ccRCC and planned for total or partial nephrectomy, or interventional diagnostic (cystoscopy and retrograde pyelography or biopsy) within 90 days from planned [68Ga]Ga-DPI-4452 administration;
21. 21_Part D, E: Adequate renal function: Estimated glomerular filtration rate (eGFR) ≥50 mL/min/1.73 m2 (as determined by the Chronic Kidney Disease – Epidemiology Collaboration - creatinine [CKDEPIcr] formula)
22. 22_Part A, B, C, D, E: WOCBP (defined as sexually mature women who have not undergone bilateral tubal ligation, bilateral oophorectomy or hysterectomy or who have not been postmenopausal) must have a negative serum pregnancy test at screening and must not be breastfeeding. Additionally, they must agree to use highly effective methods of contraception from informed consent form (ICF) signature for 6 months after the [68Ga]Ga-DPI-4452 injection (all cohorts) and for 8 months after the last 177 [Lu]Lu-DPI-4452 infusion (part B and C only). Sexual abstinence is acceptable only if it is consistent with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post-ovulation methods) and withdrawal are not acceptable methods of birth control : •A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A FSH level at screening (>40 IU/L) in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy; however, in the absence of 12 months of amenorrhea, women will be considered of childbearing potential • Permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy at least 6 months prior to first dosing or documented congenital sterility • Highly effective methods of contraception include combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion/ligation procedures, vasectomized partner, and sexual abstinence during the entire study duration if in adequation with the patient usual lifestyle. Periodic abstinence (e.g., calendar, symptothermal, post-ovulation methods) and withdrawal are not considered as a highly effective method and are not acceptable
23. 23_Part A, B, C, D, E: Sexually active men must agree to use a condom during intercourse, refrain from fathering a child during treatment period, and donate sperm for 3 months after the [68Ga]GaDPI-4452 injection (all cohorts) and for 5 months after the last [177Lu]Lu-DPI-4452 infusion (part B and C only) Female partners of childbearing potential must agree to practice sexual abstinence or be under highly effective birth control method for the above mentioned duration.
24. Part E: Regardless of lines of treatment, patients with histologically or cytologically confirmed progressive, unresectable locally advanced or metastatic solid tumors of • UC, including MIBC • HNSCC • TNBC • Squamous NSCLC • Any other indication with confirmed CA IX expression, excluding ccRCC, PDAC and CRC, upon Sponsor agreement
25. 25_Part E: Presence of at least 1 non-irradiated tumor lesion detected at conventional imaging (CT/MRI) documented within 4 weeks prior to the [68Ga]Ga-DPI-4452 administration (for scans dated more than 4 weeks prior to D1, the Sponsor should be contacted to assess conventional imaging suitability)

Exclusion criteria 21

1. 1_Part A, D, E: Known hypersensitivity to the active substance, to any of the excipients of the DPI 4452, or to radiographic contrast agents
2. 3_Part A, E: Administration of a radiopharmaceutical within a period corresponding to 10 half-lives of the radionuclide used prior to injection of [68Ga]Ga-DPI-4452
3. 4_Part A: Previous CA IX-targeting treatment
4. 5_Part A: Ongoing treatment with sulfonamides and/or coumarin derivatives (e.g., acenocoumarol, warfarin, phenprocoumon) within 2 weeks (or 5 half-lives, whichever is longer) prior to the [68Ga]Ga-DPI-4452 injection
5. 6_part A, E: Prior external beam radiation therapy (EBRT) to more than 25% of the bone marrow, as judged by the Investigator
6. 14_Part B,C: For patients included in cohorts with acetazolamide, any contra-indication to acetazolamide according to the local product label, including hypersensitivity to acetazolamide or any of its excipients or any other sulfonamides
7. 15_Part D: Renal mass known to be malignant
8. 16_Part D: Uncontrolled intercurrent illness or condition, including but not limited to ongoing or active infection, spinal cord compression, uncontrolled psychiatric disorders, or any clinically significant abnormalities detected during screening laboratory tests, ECG test or physical exams that, in the opinion of the Investigator, would adversely affect the participant's ability to participate in the study
9. 17_Part D, E: Ongoing treatment with sulfonamides and/or coumarin derivatives (e.g., acenocoumarol, warfarin, phenprocoumon) or any previous CA IX-targeting treatment within 2 weeks (or 5 half-lives, whichever is longer) prior to the [68Ga]Ga-DPI4452 injection
10. 19_Part D E: Administration of a radiopharmaceutical with therapeutic intent within a period 6 months prior to injection of [68 Ga Ga DPI-4452]
11. 7_Parts B, C: Known hypersensitivity to the active substance, to any of the excipients of the DPI 4452, or to radiographic contrast agents
12. 20_Part D,E: Patients who received any systemic antineoplastic therapy for the underlying disease and/or any other investigational study within 28 days or 5 half-life periods (whichever is shorter) prior to injection of [ 68 Ga]Ga-DPI-4452
13. 21_Part D, E: Malignant disease, other than that being treated in this study. Exceptions include the following: malignancies that were treated curatively and have not recurred within 2 years prior to screening; treated basal cell or localized squamous skin carcinomas, localized or low grade (e.g., Gleason 3+3 or 3+4 with low prostate specific antigen) prostate cancer, superficial (non-muscle invasive) urothelial cancer, localized thyroid gland microcarcinoma, other in-situ carcinoma, or other malignancy for which patients are not on active antineoplastic therapy.
14. 8_Parts B, C: Bladder outflow obstruction or unmanageable urinary incontinence
15. 9_Parts B, C: Administration of a radiopharmaceutical with therapeutic intent within a period of 6 months prior to injection of [68Ga]Ga-DPI-4452
16. 13_Parts B and C: History of active stomach or duodenum ulcer in the last 2 years, history of gastroesophageal reflux disease (GERD) Grade ≥3 according to NCI-CTCAE and/or known active gastro-intestinal infection, any unresolved prior radiation-induced gastrointestinal injury. History of gastro-intestinal toxicities from prior systemic cancer therapy not responding to medical treatment.
17. 11_Parts B, C: ongoing treatment with sulfonamides and/or coumarin derivatives (e.g., acenocoumarol, warfarin, phenprocoumon) or any previous CA IX-targeting treatment within 2 weeks (or 5 halflives, whichever is longer) prior to the [68Ga]Ga-DPI-4452 injection and [177Lu]Lu DPI 4452 infusion. Patients on stable therapeutic anticoagulation with low molecular weight heparin or direct acting oral anticoagulants without evidence of previous bleeding complications may be eligible upon agreement between Investigator and Sponsor
18. 12_Parts B, C: Prior EBRT to more than 25% of the bone marrow as judged by the Investigator
19. 2_Part A: Bladder outflow obstruction or unmanageable urinary incontinence
20. 22_Part D,E: Prior EBRT to more than 25% of the bone marrow, as judged by the Investigator
21. 23_Part D,E: Inability to stay in the scanner bed with the arms resting out of the thoracic and abdominal fields (i.e., arms alongside the body or raised arm position) for the duration of the scan

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 7

1. 1_Part A: Incidence and severity of treatment-emergent adverse events (TEAEs), serious TEAE and laboratory abnormalities graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCICTCAE) v5.0 criteria
2. 2_Part A: Change in vital signs and electrocardiogram (ECG)
3. 3_Part B: Incidence of dose-limiting toxicities (DLTs), cumulative safety, and available data including but not limited to PK data, dosimetry, changes in laboratory values, vital signs, and ECG
4. 4_Part C: Objective Response Rate (ORR) defined as the percentage of patients who achieve a partial response or complete response as measured by RECIST v1.1
5. 5_Part D: Diagnostic concordance between [68Ga]Ga-DPI-4452 uptake by PET imaging in the renal mass and assessment of the histological characteristics of the IDRM
6. 6_Part E: Radiotracer uptake at lesion level, identified via PET/CT imaging
7. 7_Part E: TBR SUVmax/SUVmean of lesion versus reference region

Secondary endpoints 44

1. 1_Part A: PK parameters of radioactivity in blood and urine
2. 2_Part A: Radioactivity uptake in normal organs and tumor lesions
3. 3_Part A: Time-Activity Curves from PET/CT images in normal organs and tumor lesions
4. 4_Part A: Whole-body radiation effective dose
5. 5_Part A: Residence time and absorbed and effective doses per organ and tumor lesion
6. 6_Part A: Radioligand [68Ga]Ga-DPI-4452 PET scan time window for optimal imaging
7. 7_Part A: Radiotracer uptake at lesion level, identified via PET/CT imaging
8. 8_Part A: TBR SUVmax/ SUVmean of lesion versus reference region
9. 9_Part A: Number and location of tumor lesions positive detected by [68Ga]Ga- DPI-4452 PET in comparison with the lesions identified by conventional imaging at baseline
10. 10_Part B: Incidence and severity of TEAEs, serious TEAEs, and laboratory abnormalities
11. 11_Part B: Incidence of treatment discontinuations and treatment modifications due to TEAEs and laboratory abnormalities
12. 12_Part B: PK parameters of radioactivity in blood and plasma and in urine
13. 13_Part B: Radioactivity absorption in normal organs and tumor lesions
14. 14_Part B: Residence time and radiation doses absorbed in organs and tumor lesions; identification of dose limiting organ(s)
15. 15_Part B: ORR as measured by RECIST v1.1
16. 16_Part B: OS for patients at the RP2D
17. 17_Part B: Semi-quantitative assessment of radiotracer absorption at lesion level, identified via whole body planar images and/or S SPECT/CT imaging in Cycle 1
18. 18_Part B: Comparison of tumor absorption versus absorption by reference region
19. 19_Part B: 68Ga SUV (max, mean) versus 177Lu absorption in tumoral lesions overall, the lesion with the highest uptake
20. 20_Part B: Concordance between [68Ga]Ga-DPI-4452 uptake by PET imaging (SUVmax, SUVmean) of the hottest lesion(s) and CA IX expression by IHC measured as H score in the available tumor biopsyy/cytological samples, and % of lesions with uptake concordant with the hottest lesion
21. 21_Part B: Radioactivity uptake in normal organs and tumor lesions estimated as radiation absorbed dose (Gy/GBq) and as SUV (max, mean)
22. 22_Part B: Time-Activity Curves from from whole body planar images and/or SPECT/CT images in normal organs and tumor lesions
23. 23_Part B: Residence time and radiation doses absorbed in organs and tumor lesions
24. 24_Part B: Number and location of tumor lesions positive detected by [68Ga]Ga- DPI-4452 PET in comparison with the standard imaging
25. 25_Part B: Incidence and severity of TEAEs, serious TEAEs, and laboratory abnormalities
26. 26_Part C: Incidence and severity of TEAEs, serious TEAEs, and laboratory abnormalities
27. 27_Part C: Incidence of treatment discontinuations and treatment modifications due to TEAEs and laboratory abnormalities
28. 28_Part C: OS
29. 29_Part C: Number and location of PET positive tumor lesions compared with the lesions identified at standard imaging (by RECIST v1.1)
30. 30_Part C: In a subset of patients: PK parameters of radioactivity in blood, plasma and in urine
31. 31_Part C: In a subset of patients: Radioactivity absorption in normal organs and tumor lesions
32. 32_Part C: In a subset of patients: Time-Activity Curves from whole body planar images and/or SPECT/CT images in normal organs and tumor lesions
33. 33_Part C: In a subset of patients: Residence time and radiation doses absorbed in organs and tumor lesions; identification of dose limiting organ(s)
34. 34_In a subset of patients: Semi-quantitative assessment of radiotracer uptake at lesion level, identified via whole body planar images and/or SPECT/CT imaging
35. 35_In a subset of patients: Comparison of tumor absorption versus absorption by reference region
36. 36_In a subset of patients: 68Ga SUV (max, mean) versus 177Lu absorption in tumoral lesions
37. 37_Part C Concordance between [68Ga]Ga-DPI-4452 uptake by PET imaging (SUVmax, SUVmean) of the hottest lesion(s) and CA IX expression by IHC measured as H score in the available tumor biopsyy/cytological samples, and % of lesions with uptake concordant with the hottest lesion
38. 38_Incidence and severity of TEAEs, serious TEAEs, and laboratory abnormalities
39. 39_Parts B, C: Change in vital signs and ECG
40. 40_Parts B, C: PFS rate at 6 months, PFS, DoR and DCR
41. 41_Part D: Sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predicitive Value (NPV) of [68Ga]GaDPI-4452 PET/CT imaging compared to histology
42. 42_Part D: Incidence and severity of TEAEs, serious TEAEs graded according to NCI-CTCAE v5.0 criteria
43. 43_Part E: Number and location of tumor lesions positive detected by [68Ga]Ga-DPI-4452 PET in comparison with the lesions identified by conventional imaging at baseline
44. 44_Part E: Incidence and severity of TEAEs, serious TEAEs graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 criteria

Investigational products

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

Test 2

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

ITM Oncologics GmbH

Sponsor organisation

ITM Oncologics GmbH

Address

Lichtenbergstrasse 1

City

Garching B. Muenchen

Postcode

85748

Country

Germany

Scientific contact point

Organisation

ITM Oncologics GmbH

Contact name

General Information

Public contact point

Organisation

ITM Oncologics GmbH

Contact name

General Information

Third parties 14

Locations

2 EU/EEA countries · 11 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 53 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