Pilot Study to Evaluate the Safety and Efficacy of 212Pb-VMT-α-peptide in Subjects With Somatostatin Receptor Expressing Neuroendocrine Tumors

Phase 2

Not yet recruiting

• Conditions: Malignant neoplasm of small intestine, (2) ICD-10 Condition: C7A8||Other malignant neuroendocrine tumors,

• Registration Number: CTRI/2023/10/059269
• Lead Sponsor: B J Madan and Company

Brief Summary

Neuroendocrine tumors (NET) are a heterogeneous group of neoplasms, arising from cells of the endocrine system, with varying clinical behaviors. Although these neoplasms are considered rare, a significant increase in the incidence and detectability of NET has been noted in many epidemiological studies in recent years.**1-4**Currently, the new pathologic classification of NEN is based on UICC/AJCC, divided NEN into well differentiated neuroendocrine tumors (NET) NET G1 (Ki-67 < 3%), G2 (Ki-67 3%-20%) and G3 (Ki-67 21%-55%), and poor differentiated neuroendocrine carcinoma(NEC) (Ki-67 > 20%). **5**Somatostatin receptor directed Peptide receptor radiotherapy (PRRT) with β-particle emitter 177Lu-DOTATATE is currently one of the more effective therapies for well differentiated gastroenteropancreatic NETs.  PRRT is fairly well tolerated without any severe adverse effects  and  has been shown to improve survival parameters. The first open, randomized, controlled trial : the NETTER-1 trial demonstrated significantly improved PFS with 177Lu-DOTATATE as compared to Octreotide LAR (Sandostatin LAR; 60 mg) (PFS 40 months vs 8.4 months) in patients with advanced midgut NET**6**. Various other trials have shown the superiority of PRRT in improving survival advantage compared to other forms of treatment including targeted therapy with mTOR or kinase inhibitor. While the results of the NETTER -1 trial led to the approval of Lu-177 DOTATATE therapy by the US FDA, PRRT with Lu177 DOTATATE has been practiced in the European countries, Australia and India for more than 25 years.PRRT with β-emitters has a good clinical effect, However, the relatively large penetration range of the β particle does result in some collateral damage to surrounding normal tissue especially the bone marrow in patients of bone metastases and normal liver parenchyma in cases of extensive hepatic metastases. The dose limits for non target tissue often limits the number of cycles of PRRT possible to a patient for the treatment of the disease.  Also, due to hypoxia cancer tissue could be resistant for β-emitters treatment. Radioisotopes emitting α-particles which have higher energy and shorter penetration range in comparison to β-particles have distinct advantages for use in targeted therapy.α-particles with high linear energy transfer (LET ≈100 keV/µm) give the higher probability of double strand breaks compared with β-particles with low LET (probability of double strand break increase ∼20 times).On the other hand, the short range (<100 µm) of α-particles in human tissue resulted in minimizing damage to surrounding healthy tissue.**7**Cell death induced by α-radiation is predominantly due to DNA double strand breaks and induced apoptosis so it is largely independent of[cell cycle phase](https://www.sciencedirect.com/topics/medicine-and-dentistry/cell-cycle-phase "Learn more about cell cycle phase from ScienceDirect’s AI-generated Topic Pages") and cell oxygenation status.**8**Due to problems of availability and production, half-life, cost and the ability to chemically and stably incorporate them into a suitable vector, only a few of α-radionuclides are medically relevant and available for potential clinical use. These include 211At, 212Bi, 213Bi, 225Ac, 223Ra, 212Pb, 227Th, and 149Tb.**8**212Pb is of definite interest because its daughter nuclides (212Bi and 212Po) undergo α-decay, which allows us to view 212Pb as an in-vivo generator of α-particles emitters. Also, Lead-212, with a convenient half-life of 10.64 h, and daughter alpha-emitter short-lived 212Bi (T1/2 = 1 h), provides the possibility for the synthesis and purification of complex radiopharmaceuticals with minimum loss of radioactivity during preparation**9**. As a benefit for clinical implementation, it can be milked from a radionuclide generator in different ways. Because 212Pb is an in-vivo generator of alpha particles, it is particularly suitable for SSTR therapy applications. VMT-α-peptide is a modified somatostatin receptor targeted peptide with improved pharmacokinetics and chelation of 203Pb/212Pb. ²¹²Pb-VMT-α-peptide is a radio-therapeutic drug indicated in subjects with unresectable, metastatic somatostatin receptor (SSTR) positive neuroendocrine tumors (NETs)**10**. The VMT chelator efficiently chelates 212Pb as well as its daughter 212Bi. Short half-lives of 212Bi daughters 208Tl and 212Po (3 min and 0.3 µs respectively) and strong chelation properties of the VMT-α-NET ensures that α-particles in the decay series are mainly emitted in the target tissue. This drug addresses an unmet need in the field of peptide receptor radionuclide therapy (PRRT) for NETs.The current study is an open ended pilot study to evaluate the safety & clinicalefficacy of targeted alpha therapy with 212Pb-VMT-α-peptide and willhelp in clinical translation of alpha PRRT with Pb212 in patients of metastaticSomatostatin Receptor Expressing Neuroendocrine Tumors.

Detailed Description

Not available

Study Timeline

• Study Start: 2023-01-12
• Last Update Posted: 2023-10-28

Recruitment & Eligibility

• Status: Not Yet Recruiting
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

• 1. Male or female ≥18 years old with unresectable or metastatic histologically confirmed NET 2) Documented progression of disease following previous therapy within 12 months prior to enrollment and the presence of at least 1 site of measurable disease per RECIST 1.1; 3) Subjects must have received and progressed following somatostatin analog administration.
• 4. Confirmed presence of somatostatin receptors on all lesions including the non-target and measurable lesions documented by CT/MRI scans, based on positive 68Ga- DOTANOC or Pb203-VMT-α-peptide SSTR PET/CT imaging within 6 weeks prior to enrollment.
• Follow up imaging will be performed with the same agent or modality used at baseline; 5) Target lesions must be positive (greater than grade 2 uptake Krenning Score) or must have an SUV of more than the normal liver background.
• 6. Lytic bone lesions, with an identifiable soft tissue component, evaluated by CT or MRI, can also be considered measurable lesions if the soft tissue component otherwise meets the definition of measurability according to RECIST 1.1. In any case, osteoblastic bone lesions are not measurable.
• 7. Eastern Cooperative Oncology Group (ECOG) status 0-2.
• 8. Life expectancy of at least 12 weeks in the opinion of the investigator at the time of screening; 9) Be willing to practice the following medically acceptable methods of birth control (both women of childbearing potential (WOCBP) and men who have partners of childbearing potential) from the Screening Visit through 3 months after the final administration 212Pb- VMT-α-peptide.
• 10. Sufficient bone marrow capacity and organ function in the recent blood tests within 3 weeks prior to Day 1, as defined by: a) White blood cell (WBC) ≥2,500/ mm3; b) Absolute neutrophil count (ANC) ≥1000/mm3; c) Platelets ≥100,000/mm3; d) Hemoglobin (HgB) ≥9.0 g/dL; e) Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) ≤3 X upper limit of normal (ULN); f) Total Bilirubin: ≤2 X ULN; g) Serum creatinine ≤1.7 mg/dL; h) Serum albumin ≥3.0 g/L; if lower than 3.0 g/L requires normal range prothrombin time (PT) and international normalized ratio (INR).

Exclusion Criteria

• 1. Prior whole-body radiotherapy or PRRT using 177Lu/90Y/111In-DOTATATE/ DOTATOC or TAT.
• 2. Prior regional hepatic radionuclide therapy within 4 months prior to enrollment or prior nonradioactive regional hepatic therapy within 6 months prior to enrollment.
• 3. Known hypersensitivity to somatostatin analogues, AA infusion, or 212Pb-VMT-α-peptide; 4) Therapeutic use of any somatostatin analogue, including Sandostatin® LAR (within 28 days) and Sandostatin® (within 1 day) prior to administration of study drug; 5) History of myelodysplastic syndrome (MDS); 6) Female subjects who are pregnant or lactating; 7) Indication for surgical lesion removal with curative potential; 8) Known brain metastases, unless these metastases have been treated and/or stable for 6 months prior to enrollment; 9) Experimental cancer treatments or other investigational therapies within 6 weeks or five half-lives of the investigational medication prior to Day 1; 10) Uncontrolled congestive heart failure (NYHA II, III, IV); 11) Uncontrolled diabetes mellitus as defined by a hemoglobin A1C >10.0; 12) Evidence of renal obstruction based on Tc-99m DTPA or TER for MAG3 renal scintigraphy or renal ultrasound.
• 13. Known or active human immunodeficiency virus (HIV) or hepatitis B or C virus unless cured; 14) Known or suspected active drug or alcohol abuse; 15) Participation in other interventional clinical studies within 30 days prior to Day 1; 16 Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in situ of the uterine cervix, unless definitively treated and proven no evidence of recurrence for 5 years; 16) Any somatic or psychiatric disease/condition or abnormal laboratory test that in the opinion of the investigator, may interfere with the objectives and assessments of the study; or 17) Unable to comply with the requirements of the study protocol or be unsuitable for the study for any reason, in the opinion of the investigator.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
•The morphological imaging (CT/MRI) will be done before therapy and selected time points before therapy cycle to determine changes in the size of target lesions.	Every 6 months
•Measurement of the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. [ Time Frame: 24 months after last dose administration ]	Every 6 months
•Number of patients with treatment-related adverse events as assessed by CTCAE v.4.0 [ Time Frame: 24 months after last dose administration ]	Every 6 months

Secondary Outcome Measures

Name	Time	Method
•Measurement of the Median Progression free survival (mPFS) [ Time Frame: 24 months after last dose administration ]	•PFS will be defined as the number of days from the first dose of 212Pb- VMT-α-peptide to documented tumor progression per RECIST 1.1 criteria or death due to any cause.

Trial Locations

Locations (1)

Fortis Memorial Research Institute, Gurugram; 🇮🇳 Gurgaon, HARYANA, India

Fortis Memorial Research Institute, Gurugram

🇮🇳Gurgaon, HARYANA, India

Dr Ishita Sen

Principal investigator

9811127080

ishita.sen@fortishealthcare.com