Safety, Tolerability, PK, Dosimetry, MTD and Preliminary Efficacy of Intra-lesionally Injected AvidinOX, Followed by IV Escalating Doses of [177Lu]DOTA-biotin in Pts With Injectable Solid Tumors or Lymphomas

Study Overview
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Brief Summary
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Local treatment of unresectable tumors is challenging, particularly with radioactivity. Current practice relies on external beam irradiation or on a variety of medical devices for brachytherapy. Both approaches proved useful in controlling tumor growth but are characterized by poor patient's compliance, significant side effects, high costs and technological complexity hampering wide-spread use. The use of AvidinOX for radionuclide therapy of inoperable cancer lesions will offer a number of advantages compared to current brachytherapy. In fact, the perfusion of a target tissue with AvidinOX, compared to current devices, will allow adapting the therapy to the tumor/organ shape, and it will also make it possible to delay the administration of radioactivity for several days which, according to pre-clinical studies, might be also divided up into repeated doses. AvidinOX linking stably to tissue proteins, does not exhibit the problem of seed migration which is associated with high morbidity. Based on previous findings with AvidinOX in combination with radionuclides in pre-clinical studies as well as data from the clinical use in liver metastases, it can be assumed that intralesional injections of AvidinOX followed by intravenous injections of 177Lu-ST2210 could be a safe and efficacious method for treating inoperable tumor lesions.

Detailed Description
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The primary objectives of this study are: To identify the Maximum Tolerated Dose (MTD) of two consecutive repeated IV 177Lu-ST2210 administration following a previous tumor intra-lesion/s injection of AvidinOX. To assess safety and tolerability of intra-lesionally injected AvidinOX + IV injected 177Lu-ST2210 To evaluate intra-lesional distribution and retention of {AvidinOX + 177Lu-ST2210}-complex in tumor lesion/s To evaluate systemic biodistribution and pharmacokinetics of 177Lu-ST2210 and {AvidinOX + 177Lu-ST2210}- complex Main secondary objectives are: To evaluate whole body dosimetry of IV 177Lu-ST2210 after prior AvidinOX injection (radiation safety dosimetry) To record individual tumor dosimetry To evaluate preliminary efficacy of {AvidinOX + 177Lu-ST2210}-complex in reducing tumor size and metabolic activity. To evaluate damage of tumor cells by radioactivity and immunogenic cell death To evaluate whole body safety dosimetry and dose linearity To evaluate pharmacokinetics of ST2210 in plasma and urine

Official Title
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A Dose Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, Dosimetry, Maximum Tolerated Dose and Preliminary Efficacy of Intra-lesionally Injected AvidinOX, Followed by Systemic IV Administration of Escalating Doses of [177Lu]DOTA-biotin in Patients With Solid Tumors or Lymphomas With Injectable Neoplastic Lesions.

Conditions
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Inoperable Solid Tumors or Lymphomas

Intervention / Treatment
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* Drug: AvidinOX
* Drug: 177Lu-ST2210
* Drug: 177Lu-ST2210


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Presence of inoperable tumor lesion/s from histologically confirmed solid tumors or lymphomas, in patients with at least one lesion ≥ 1 cm and suitable for intra-lesional injection, who have disease progression after treatment with available therapies, or who are intolerant to such treatments Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 If the patient received previous radiation therapy, the total absorbed radiation dose at the bone marrow level must be ≤ 1 Gy Life expectancy of at least 3 months Total tumor burden requiring ≤ 75 mL AvidinOX injection Clotting parameters within normal limits or maximum 25% outside of the the normal ranges Haematological and liver function test results ≤ grade 2 toxicity (according to US National Cancer Institute's Common Terminology) Criteria for Adverse Events v4.03 [CTCAE Urine protein (dipstick): negative or trace; in case of trace, a urinalysis has to be performed in the local laboratory and have to confirm that such abnormality is not to be considered clinically significant, according to the investigator's judgement Creatinine ≤ 1.7 mg/dL eGFR> 60% of mean age adjusted normal values Written informed consent Main Exclusion Criteria: Known hypersensitivity to Avidin or AvidinOX (e.g. hen egg) Known hypersensitivity to ST2210 (DOTA biotin) or any excipient. Presence of unreachable (e.g. located in a region that cannot be reached by needle) or untreatable tumor lesions so that the benefit from the treatment of the treatable lesions does not justify patient's inclusion Active infection at screening or history of severe infection within the previous 3 months, if clinically relevant at screening as considered by the investigator Known human immunodeficiency virus (HIV) positive serology or chronically active hepatitis B or C. Administration of another investigational medicinal product within 30 days before the screening period. Patient who underwent chemotherapy, radiation therapy within 15 days before the screening period Previous treatment with any radiopharmaceutical within a period corresponding to 8 half-lives of the radionuclide used for labeling the respective radiopharmaceutical prior to the administration of study drug. Women of child-bearing potential without a serum negative pregnancy test and not willing to refrain from sexual activity or to utilize an adeguate contraceptive methods during all the course of the study Men unwilling to use appropriate contraceptive methods during the study and up to six months follow-up period

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
Intervention Model: Single Group Assignment
Interventional Model Description: 3 + 3 dose escalation design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AvidinOX/177Lu-ST2210<br>Patients will receive an intralesion injection of AvidinOX followed by two intravenous infusions of 177Lu- ST2210 with a distance of 14 days between them | Drug: AvidinOX<br>* AvidinOX vial containing 22.5 mg AvidinOX + vials containing 10 ml of water for injection (WFI) for the reconstitution in a clear solution with an AvidinOX concentration of 3 mg/ml. One Intralesion administration of a volume of reconstituted AvidinOX equal to about 15 % of the estimated lesion volume<br>Drug: 177Lu-ST2210<br>* 177Lu-ST2210 dose starting at 7.5 Gigabequerel (GBq) ±10%with escalation steps of 2.5 GBq up to 15 GBq ±10%, approximately 1 mg ST2210<br>Drug: 177Lu-ST2210<br>* Second dose of 177Lu-ST2210 dose (14 days after the first dose) starting at 7.5 Gigabequerel (GBq) ±10%with escalation steps of 2.5 GBq up to 15 GBq ±10%, approximately 1 mg ST2210<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity evaluated using NCI Common Toxicity Criteria (CTCAE 4.03) |  | Up to six weeks after the second 177Lu-ST2210 infusion |