| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Solid tumors known to overexpress GRPR and with [68Ga]-NeoB lesion uptake |
|
| E.1.1.1 | Medical condition in easily understood language |
| Solid tumors expressing a specific target (GRPR) identified by [68Ga]-NeoB and for treatment with [177Lu]-NeoB |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase I:
• To identify the maximum tolerated dose (MTD) and/or Recommended Phase II dose (RP2D) of [177Lu]-NeoB
Phase IIa:
• Cohort A, B, C: To assess the Disease Control Rate (DCR) of [177Lu]-NeoB at the RP2D
• Cohort D: To assess the PK as well as the biodistribution and radiation dosimetry of [177Lu]-NeoB in patients with moderately impaired renal function
|
|
| E.2.2 | Secondary objectives of the trial |
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
Phase IIa:
• Cohort A, B, C: To assess quality of life of patients via EORTC QLQ-C30 Questionnaire
• Cohort A, B, C: To assess the PK as well as the biodistribution and radiation dosimetry of [177Lu]-NeoB
• Cohort A, B, C: To further assess the anti-tumor activity of [177Lu]-NeoB
Phase I and IIa:
• To characterize the safety and tolerability of [177Lu]-NeoB
• To further characterize the safety and tolerability of [68Ga]-NeoB
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed informed consent must be obtained prior to participation in the study.
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 and HER-2 low based on current practice and medical history
b. Cohort B: Prostate cancer
c. Cohort C: GIST
d. Cohort D: patients affected by any advanced/metastatic solid tumor type suspected 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
3. At least one measurable lesion per RECIST 1.1, RANO (applicable for GBM only) criteria detected on the low-dose CT/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. 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, 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. Patient Eastern Cooperative Oncology Group (ECOG) performance status:
For phase I: ≤ 2
For phase IIa: ≤ 1
|
|
| E.4 | Principal exclusion criteria |
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. 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 and C)
b. <30 mL/min and ≥ 60 mL/min for Phase IIa (Cohort D)
3. Platelet count of < 75 x 10^9/L
4. Absolute neutrophil count (ANC) < 1.0 x 10^9/L.
5. Hemoglobin < 9 g/dL
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
7. Total bilirubin > 1.5 x ULN, except for patients with documented Gilbert’s syndrome who are eligible if total bilirubin ≤ 3 x ULN
8. Serum amylase and/or lipase > 1.5 x ULN
9. Known or expected hypersensitivity to [177Lu]-NeoB, [68Ga]-NeoB or any of their excipients.
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.
11. Patients with diabetes mellitus not stable under current treatment as judged by the investigator or with hyperglycemia ≥ CTCAE version 5.0 Grade 2
12. Patients with history of or ongoing acute or chronic pancreatitis.
13. Concurrent bladder outflow obstruction or unmanageable urinary incontinence.
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).
15. Prior External Beam Radiation Therapy (EBRT) to more than 25% of the bone marrow.
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).
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, mitomycin-C) 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
19. History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study.
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.
21. Pregnant or breast-feeding women
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 include are discussed in the protocol.
23. Use of other investigational drugs within 30 days prior to informed consent signature.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I
• Incidence and nature of dose limiting toxicities (DLTs)
Phase IIa
• DCR as assessed by Response Evaluation Criteria In Solid Tumors
(RECIST v1.1)
Cohort D:
• 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 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I
• End of DLT period of last patient (each cohort)
Phase IIa
Cohorts A, B, C:
• as assessed by Response Evaluation Criteria In Solid Tumors (RECIST v1.1)
Cohort D:
Last patient last visit |
|
| E.5.2 | Secondary end point(s) |
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)
• 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)
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
• Objective response rate (ORR), Duration of Response (DOR), Progression Free Survival (PFS) as assessed by RECIST version 1.1 and OS
Phase I and IIa:
• Adverse events, serious adverse events, changes in hematology and chemistry values, vital signs, ECGs
• Dose interruptions and modifications
• Adverse events, serious adverse events |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase I
• During Cycle 1 of [177Lu]-NeoB
Phase IIa
• Cohorts A,B,C:
- During Cycle 1 of [177Lu]-NeoB for dosimetry and PK
- After each cycle of [177Lu]-NeoB and 6 weeks after EoT for EORTC
- Every 10 weeks after the first treatment with [177Lu]-NeoB until disease progression or end of the trial whichever comes first, for ORR, DOR and PFS
Phase I and IIa:
- During treatment phase until end of long term follow up |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| Austria |
| Netherlands |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the clinical trial is defined as the last visit of the last patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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