NeoRay - Phase I/IIa trial of [177Lu]-NeoB in patients with advanced solid tumors and with [68Ga]-NeoB lesion uptake.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Advanced Accelerator Applications International S.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

29 Jul 2019 → 28 Nov 2025

Decision date (initial)

2024-07-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Advanced Accelerator Applications International S.A.

External identifiers

EU CT number

2023-507170-41-00

EudraCT number

2018-004727-37

ClinicalTrials.gov

NCT03872778

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic, Others, Efficacy, Safety

Phase I: To identify the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of [177Lu]-NeoB.
Phase IIa: Cohorts A, B, C: To assess the anti-tumor activity of [177Lu]-NeoB at the RP2D across different solid tumors; Cohort E: To assess the PK as well as the biodistribution and radiation dosimetry of [177Lu]-NeoB when co-administered with the neprilysin inhibitor (NEPi) LCZ696 in Cycle 1 (only performed in the US and UK).

Secondary objectives 3

1. Phase I: - To assess the PK as well as the biodistribution and radiation dosimetry of each Dose level of [177Lu]-NeoB. - To assess the preliminary anti-tumor activity of [177Lu]-NeoB.
2. Phase IIa: - Cohorts A, B, C: To assess the PK as well as the distribution and radiation dosimetry of [177Lu]-NeoB. - Cohorts A, B, C: To assess quality of life of patients via EORTC QLQ-C30 Questionnaire. - Cohort E: To characterize the safety and tolerability of [177Lu]-NeoB when co-administered with the NEPi LCZ696 in Cycle 1 (only performed in the US and UK).
3. Phase I and Phase IIa: - To characterize the safety and tolerability of [177Lu]-NeoB as monotherapy. - To further characterize the safety and tolerability of [68Ga]-NeoB.

Conditions and MedDRA coding

Solid tumors known to overexpress GRPR and with [68Ga]-NeoB lesion uptake.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. 1. Signed informed consent must be obtained prior to participation in the study.
2. 2. Adult patients (age ≥ 18 years old) with any of the following advanced or metastatic solid tumors: - For Phase I: breast cancer, lung cancer, prostate cancer, GIST, GBM. - For Phase IIa: a. Cohort A: Breast cancer with histology as follows: HR-positive with ER > 10% of nuclei stain, HER-2 negative including HER-2 low as assessed on the primary diagnosis. b. Cohort B: Prostate cancer. c. Cohort C: GIST. d. Cohort D: patients affected by any advanced/metastatic solid tumor type known to overexpress GRPR including recurrent GBM, and with moderate impaired renal function defined as creatinine clearance (calculated using the Cockcroft-Gault formula, or measured) ≥ 30mL/min and < 60mL/min. e. Cohort E: only performed in the US and UK.
3. 3. At least one measurable lesion per RECIST 1.1, RANO (applicable for GBM only) criteria detected on the low dose CT or on the MRI (for GBM MRI only) acquired together with the [68Ga]-NeoB PET. The same identified measurable lesion shows [68Ga]-NeoB uptake on PET/CT or PET/MRI. If the only matching lesion is located in the bone, the patient will still be eligible.
4. 4. Patients for whom no standard therapy is available, tolerated or appropriate in both Phase I and Phase IIa. Specifically in the Phase IIa breast cancer cohort A, patients need to have completed at least one prior treatment of endocrine therapy (including CDk4/6i) and at least one prior chemotherapy (unless contraindicated) in the metastatic setting. Patients with prior treatment with trastuzumab deruxtecan, alpelisib or elascestrant are also eligible. In case of confirmed presence of deleterious or suspected deleterious germline BRCA1 or BRCA2 mutation, the patient must also have already received a PARP inhibitor based therapy.
5. 5. Patient Eastern Cooperative Oncology Group (ECOG performance status: - For phase I: ≤ 2. - For phase IIa: ≤ 1.

Exclusion criteria 23

1. 1. Patients who have not had resolution, except where otherwise stated in the inclusion/ exclusion criteria, of all clinically significant toxic effects of prior systemic cancer therapy, surgery, or radiotherapy to Grade ≤1 (except for alopecia).
2. 2. Creatinine clearance (calculated using Cockcroft-Gault formula, or measured): a. < 60 mL/min or serum creatinine > 1.5 x ULN for Phase I and Phase IIa (Cohort A, B, C and E). b. <30 mL/min and ≥ 60 mL/min for Phase IIa (Cohort D).
3. 3-4-5. Platelet count of < 75 x 10^9/L. Absolute neutrophil count (ANC) < 1.0 x 10^9/L. Hemoglobin < 9 g/dL.
4. 6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x upper limit of normal (ULN) if no demonstrable liver metastases or > 5 x ULN in the presence of liver metastases.
5. 7. Total bilirubin > 1.5 x ULN, except for patients with documented Gilbert's syndrome who are eligible if total bilirubin ≤ 3 x ULN.
6. 8. Serum amylase and/or lipase > 1.5 x ULN.
7. 9. Known or expected hypersensitivity to [177Lu]-NeoB, [68Ga]-NeoB or any of their excipients.
8. 10. Impaired cardiac function or clinically significant cardiac disease, including any of the following: - Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (NYHA grade ≥ 2), uncontrolled arterial hypertension or clinically significant arrhythmia. - LVEF < 50% as determined by echocardiogram (ECHO). - QTcF >470 msec for females and QTcF >450 msec for males on screening electrocardiogram (ECG) or congenital long QT syndrome. - Acute myocardial infarction or unstable angina pectoris < 3 months prior to [177Lu]-NeoB (IMP1) administration.
9. 11. Patients with diabetes mellitus not stable under current treatment as judged by the investigator or with hyperglycemia ≥ CTCAE version 5.0 Grade 2.
10. 12. Patients with history of or ongoing acute or chronic pancreatitis.
11. 13. Concurrent bladder outflow obstruction or unmanageable urinary incontinence.
12. 14. Administration of a radiopharmaceutical with therapeutic intent within a period corresponding to 10 half-lives of the radionuclide used prior to injection of [68Ga]-NeoB (IMP2).
13. 15. Prior External Beam Radiation Therapy (EBRT) to more than 25% of the bone marrow.
14. 16. [223Ra]-therapy within the context of diffuse bone or bone-marrow involvement (i.e. "superscan" defined as bone scintigraphy in which there is excessive skeletal radioisotope uptake [>20 bone lesions] in relation to soft tissues along with absent or faint activity in the genitourinary tract due to diffuse bone/ bone marrow metastases).
15. 17. [Removed]
16. 18. Patients who have received prior systemic anti-cancer treatment within the following time frames: - Cyclical chemotherapy within a period that is shorter than the cycle length used for that treatment (e.g. 6 weeks for nitrosourea, mitomycinC) prior to starting [177Lu]-NeoB treatment. - Biologic therapy (e.g. antibodies), continuous or intermittent small molecule therapeutics, or any other investigational agents within a period which is ≤ 5 T1/2 or ≤ 14 days (whichever is shorter) prior to starting [177Lu]-NeoB treatment.
17. 19. History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study.
18. 20. Malignant disease, other than that being treated in this study. Exceptions to this exclusion include the following: malignancies that were treated curatively and have not recurred within 2 years prior to [177Lu]-NeoB treatment; completely resected basal cell and squamous cell skin cancers; any malignancy considered to be indolent and that has never required therapy; and completely resected carcinoma in situ of any type.
19. 21. Pregnant or breast-feeding women.
20. 22. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, are not allowed to participate in this study UNLESS they are using highly effective methods of contraception throughout the study and for 7 months after study drug discontinuation. Highly effective contraception methods are discussed in the protocol.
21. 23. Use of other investigational drugs within 30 days prior to informed consent signature.
22. 24. Cohorts A, B, C: Patient currently receiving NEP inhibitors (e.g., Entresto, racecadotril) and for whom images for dosimetry assessments cannot be acquired.
23. 25. Cohort E only: only performed in the US and UK.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Phase I: Incidence and nature of dose limiting toxicities (DLTs).
2. Phase IIa: - Cohorts A, B, C: Individual clinical responses assessed by Response Evaluation Criteria In Solid Tumors (RECIST v1.1). - Cohort E only: only performed in the US and UK.

Secondary endpoints 5

1. Phase I: • Tissue Activity Curves (ACs) generated from the amount of radioactivity in one given tissue at a given moment over the amount of radioactivity present in the blood at that given moment • Time ACs, describing % of the activity amount injected vs. time will be derived • Absorbed radiation doses of [177Lu]-NeoB in critical organs (e.g. kidneys, bone marrow, pancreas)
2. Phase I: • Urinary excretion of [177Lu]-NeoB • Half-life of [177Lu]-NeoB in blood • Residence times of [177Lu]-NeoB in organs and tumor lesions • Individual objective response and Duration of Response (DOR)
3. Phase IIa Cohorts A, B, C: • Absorbed radiation doses of [177Lu]-NeoB in organs and tumor lesions based on TACs • Concentration of [177Lu]-NeoB in blood over time and derived PK parameters • Changes from baseline in EORTC QLQ-C30
4. Phase IIa Cohort E only: (only performed in the US and UK) • Adverse events, serious adverse events, changes in hematology and chemistry values, vital signs, ECGs • Dose interruptions and modifications
5. Phase I and IIa: • Adverse events, serious adverse events, changes in hematology and chemistry values, vital signs, ECGs • Dose interruptions and modifications

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Advanced Accelerator Applications International S.A.

Sponsor organisation

Advanced Accelerator Applications International S.A.

Address

Rue De La Tour-De-L'ile 4

City

Geneva

Postcode

1204

Country

Switzerland

Scientific contact point

Organisation

Advanced Accelerator Applications International S.A.

Contact name

Advanced Accelerator Applications International SA - Regulatory Affairs

Public contact point

Organisation

Advanced Accelerator Applications International S.A.

Contact name

Advanced Accelerator Applications International SA - Regulatory Affairs

Third parties 4

Locations

4 EU/EEA countries · 4 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 6 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications