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

Study Overview
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Brief Summary
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The main purpose of Part A of the study is to evaluate safety, tolerability and tracer uptake after a single intravenous (IV) administration of [68Ga]Ga-DPI-4452; Part B: is to determine the recommended phase 2 dose (RP2D) [maximum tolerated dose (MTD) or lower dose] for [177Lu]Lu-DPI-4452 for each tumor type; Part C: is to evaluate the preliminary antitumor activity of [177Lu]Lu-DPI-4452 as monotherapy.

Official Title
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A Multicenter, Open-Label, Non-Randomized Phase 1/2 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 Patients With Unresectable Locally Advanced or Metastatic Solid Tumors

Conditions
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Clear Cell Renal Cell Cancer (ccRCC), Pancreatic Ductal Adenocarcinoma (PDAC), Colorectal Cancer (CRC)

Intervention / Treatment
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* Drug: [68Ga]Ga-DPI-4452
* Drug: [177Lu]Lu-DPI-4452


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A, B and C: Written informed consent, dated and signed by the patient prior to any study-specific procedure Has histologically or cytologically confirmed, unresectable locally advanced or metastatic solid tumors of: clear cell renal cell cancer (ccRCC) - participants must have received at least one line containing Tyrosine kinase inhibitor (TKI) treatment and at least one line containing Immune Checkpoint Inhibitor treatment in metastatic setting, meaning at least two lines of treatment in metastatic setting, pancreatic ductal adenocarcinoma (PDAC) - participants must have received at least one line of platinum- and/or gemcitabine based regimen; or colorectal cancer (CRC) - participants must have received at least one line of FOLFIRINOX or FOLFOX/FOLFIRI in two lines in combination with anti-Vascular Endothelial Growth Factor (VEGF) or anti-Epidermal Growth Factor Receptor (EGFR). Participants with CRC or PDAC: availability of fresh biopsy, OR an archival biopsy/surgical specimen of the tumor (preferably, taken after last prior line of therapy). Presence of at least 1 non-irradiated tumor lesion detected at conventional imaging (computed tomography / magnetic resonance imaging (CT/MRI)) documented within 4 weeks prior to the [68Ga]Ga-DPI-4452 administration. Measurable disease per response evaluation criteria in solid tumors (RECIST) v1.1 Exclusion Criteria: Any major surgery within 12 weeks before enrollment 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 Part A: Has known hypersensitivity to the active substance, to any of the excipients of the DPI-4452, or to radiographic contrast agents. Bladder outflow obstruction or unmanageable urinary incontinence. Participants who have not had resolution of clinically significant toxic effects of prior systemic cancer therapy, surgery, or radiotherapy to Grade ≤1 (except for laboratory parameters specified above, Grade 2 alopecia, and/or stable Grade 2 sensory neuropathy, according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCI-CTCAE]). Administration of a radiopharmaceutical within a period corresponding to 10 half-lives of the radionuclide used prior to injection of [68Ga]Ga-DPI-4452. Previous Carbonic anhydrase (CA) IX-targeting treatment. Prior external beam radiation therapy (EBRT) to more than 25% of the bone marrow, as judged by the Investigator. Part B and Part C: Known hypersensitivity to the active substance, to any of the excipients of the DPI-4452, or to radiographic contrast agents. Bladder outflow obstruction or unmanageable urinary incontinence. Participants who have not had resolution of clinically significant toxic effects of prior systemic cancer therapy, surgery, or radiotherapy to Grade ≤1 (except for laboratory parameters specified above, Grade 2 alopecia, or stable Grade 2 sensory neuropathy, according to NCI-CTCAE). Administration of a radiopharmaceutical with therapeutic intent within a period of 6 months prior to injection of [68Ga]Ga-DPI-4452. Any previous CA IX-targeting treatment for more than 1 cycle or 1 month. Participants who received any systemic antineoplastic therapy for the underlying disease and/or other investigational agents within a period which is ≤5 half-lives or ≤4 weeks (whichever is shorter). Inflammatory bowel disease (e.g Crohn's disease, ulcerative colitis, etc). Note: Other inclusion/exclusion criteria mentioned in the protocol may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: [68Ga]Ga-DPI-4452<br>Participants will receive [68Ga]Ga-DPI-4452, a single dose on Day 1. | Drug: [68Ga]Ga-DPI-4452<br>* [68Ga]Ga-DPI-4452, administered as IV injection.<br>|
| Experimental: Part B: [177Lu]Lu-DPI-4452<br>Participants will receive a single dose of [68Ga]Ga-DPI-4452, at screening then escalating doses of [177Lu]Lu-DPI-4452, on Day 1 of each 28-cycle and RP2D will be determined. | Drug: [68Ga]Ga-DPI-4452<br>* [68Ga]Ga-DPI-4452, administered as IV injection.<br>Drug: [177Lu]Lu-DPI-4452<br>* [177Lu]Lu-DPI-4452, administered as IV infusion.<br>|
| Experimental: Part C: [177Lu]Lu-DPI-4452<br>Participants will receive a single dose of [68Ga]Ga-DPI-4452, at screening and RP2D dose of [177Lu]Lu-DPI-4452, on Day 1 of each 28-day cycle during the treatment period. | Drug: [68Ga]Ga-DPI-4452<br>* [68Ga]Ga-DPI-4452, administered as IV injection.<br>Drug: [177Lu]Lu-DPI-4452<br>* [177Lu]Lu-DPI-4452, administered as IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | Up to Day 7 | 
| Part B: Number of Participants Experiencing Dose-Limiting Toxicities (DLTs) |  | Cycle 1 (28 days) | 
| Part C: Objective Response Rate (ORR) |  | Up to approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Concentration of [68Ga]Ga-DPI-4452 in Blood | Pharmacokinetics (PK) will be evaluated in blood for radioactivity of [68Ga]Ga-DPI-4452. | Pre-dose and at multiple time points up to 4 hours post-dose on Day 1 | 
| Part A: Radioligand [68Ga]Ga-DPI-4452 Positron Emission Tomography (PET) Scan Time-Window for Optimal Imaging |  | Day 1 | 
| Part B: Objective Response Rate (ORR) |  | Up to approximately 2 years | 
| Parts B and C: Concentration of [177Lu]Lu-DPI-4452 in Blood and Plasma | PK will be evaluated in blood and plasma for radioactivity of [177Lu]Lu-DPI-4452. | Pre-dose and at multiple time points up to 72 hours post-dose of Cycles 1, 2 and 3 (84 days) {each cycle= 28 days} | 
| Parts B and C: Progression Free Survival (PFS) Rate at 6 Months |  | 6 months | 
| Parts B and C: Progression Free Survival (PFS) |  | Up to approximately 2 years | 
| Parts B and C: Overall Survival (OS) |  | Up to approximately 2 years | 
| Parts B and C: Duration of Response (DoR) |  | Up to approximately 2 years | 
| Parts B and C: Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) |  | Up to approximately 2 years | 
| Parts A, B and C: Concentration of [68Ga]Ga-DPI-4452 and [177Lu]Lu-DPI-4452 in Urine | PK will be evaluated in urine for radioactivity of [68Ga]Ga-DPI-4452 and [177Lu]Lu-DPI-4452. | Part A: Pre-dose and at multiple time points up to 4 hours post-dose on Day 1; Part B: Cycle 1 (each cycle= 28 days); Part C: Pre-dose and at multiple time points up to 24 hours post-dose of Cycle 1 (each cycle= 28 days) | 
| Parts A, B and C: Number of Positive Tumor Lesions Detected by Imaging |  | Part A: Day 1; Part B and C: Baseline | 
| Parts B and C: Disease Control Rate (DCR) |  | Up to approximately 2 years | 
| Parts A, B and C: Human Dosimetry [68Ga]Ga-DPI-4452 | Whole body effective dose will be calculated using the PET scan. | Part A: Day 1; Parts B and C: Cycle 1 (each cycle= 28 days) |