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

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.

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.

Study Overview

• Status: Terminated
• Conditions: Inoperable Solid Tumors or Lymphomas
• Intervention / Treatment: Drug: AvidinOX; Drug: 177Lu-ST2210; Drug: 177Lu-ST2210

Detailed Description

The primary objectives of this study are:

1. 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.
2. To assess safety and tolerability of intra-lesionally injected AvidinOX + IV injected 177Lu-ST2210
3. To evaluate intra-lesional distribution and retention of {AvidinOX + 177Lu-ST2210}-complex in tumor lesion/s
4. To evaluate systemic biodistribution and pharmacokinetics of 177Lu-ST2210 and {AvidinOX + 177Lu-ST2210}- complex

Main secondary objectives are:

1. To evaluate whole body dosimetry of IV 177Lu-ST2210 after prior AvidinOX injection (radiation safety dosimetry)
2. To record individual tumor dosimetry
3. To evaluate preliminary efficacy of {AvidinOX + 177Lu-ST2210}-complex in reducing tumor size and metabolic activity.
4. To evaluate damage of tumor cells by radioactivity and immunogenic cell death
5. To evaluate whole body safety dosimetry and dose linearity
6. To evaluate pharmacokinetics of ST2210 in plasma and urine

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Dep. of Investigational Cancer Therapeutics - U. T. M. D. Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: AvidinOX/177Lu-ST2210; 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; 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; Drug: 177Lu-ST2210; 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; Drug: 177Lu-ST2210; 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

What is the study measuring?

Primary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Alfasigma S.p.A.
• Investigators: Principal Investigator: Vivek Subbiah, MD, Dep. of Investigational Cancer Therapeutics - U. T. M. D. Anderson Cancer Center

Publications and helpful links

General Publications

• Vesci L, Carollo V, Rosi A, De Santis R. Therapeutic efficacy of intra-tumor AvidinOX and low systemic dose biotinylated cetuximab, with and without cisplatin, in an orthotopic model of head and neck cancer. Oncol Lett. 2019 Mar;17(3):3529-3536. doi: 10.3892/ol.2019.10003. Epub 2019 Feb 1.

Study record dates

Study Major Dates

• Study Start (Actual): August 7, 2017
• Primary Completion (Actual): June 30, 2019
• Study Completion (Actual): July 1, 2019

Study Registration Dates

• First Submitted: June 13, 2017
• First Submitted That Met QC Criteria: June 14, 2017
• First Posted (Actual): June 15, 2017

Study Record Updates

• Last Update Posted (Actual): July 5, 2019
• Last Update Submitted That Met QC Criteria: July 1, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma
• Other Study ID Numbers: AvOX/ST2210-CR-15-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No