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About
The purpose of this first-in-human (FIH) study of [177Lu]-NeoB is to characterize the safety, tolerability, pharmacokinetics (PK) as well as the distribution and radiation dosimetry, and anti-tumor activity of [177Lu]-NeoB in patients with advanced solid tumors known to overexpress Gastrin-Releasing Peptide Receptor (GRPR) and with [68Ga]-NeoB lesion uptake.
Full description
This is a Phase I/IIa study which consists of a dose escalation (Phase I) and an expansion part (Phase IIa).
Dose escalation (Phase I):
Phase I study will be conducted in adult patients (age >= 18 years old) with any of the following selected advanced or metastatic solid tumors: breast cancer, lung cancer, prostate cancer, gastro intestinal stromal tumor (GIST), and glioblastoma (GBM) for whom no standard therapy is available, tolerated or appropriate, and with [68Ga]-NeoB lesion uptake as defined in the inclusion criteria.
In Phase I, every effort must be made to include at least one patient of each gender (male/female) in each Dose level to obtain dosimetry data for each gender at all Dose levels tested. However, if it is not feasible, at least 3 patients of each gender must be included in the study before reaching the [177Lu]-NeoB Dose level of 100% estimated cumulative dose (ECD) (Dose level 4) or the maximum tolerated dose (MTD) / recommended phase two dose (RP2D), whichever is lower.
Expansion part (Phase IIa):
The Phase IIa study will be conducted in adult patients (age >= 18 years old) with:
For Cohorts A, B, C respectively: Any of the following selected advanced or metastatic solid tumors: breast cancer (human receptor (HR)-positive, human epidermal growth factor receptor-2 (HER-2) negative including HER 2 low), prostate cancer, and GIST all showing [68Ga]-NeoB lesion uptake.
For 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.
For Cohort E (US and UK only): Patients eligible for enrollment in any of the three advanced/metastatic tumor types (as defined for Cohorts A, B, C) who will receive the first cycle of [177Lu]-NeoB upon co-administration with LCZ696
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Signed informed consent must be obtained prior to participation in the study.
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:
Cohort A: Breast cancer with histology as follows: HR positive with ER > 10% of nuclei stain, HER-2 negative including HER-2 low based on current practice and medical history
Cohort B: Prostate cancer
Cohort C: GIST
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) ≥ 30 mL/min and < 60 mL/min
** Enrollment in cohort D will no longer be allowed with implementation of protocol version 07. **
Cohort E: 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, or prostate cancer, or GIST
At least one measurable lesion as 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.
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.
Patient Eastern Cooperative Oncology Group (ECOG) performance status:
Exclusion criteria
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)*.
Creatinine clearance (calculated using Cockcroft-Gault formula, or measured)
Platelet count of < 75 x 109/L*†
Absolute neutrophil count (ANC) < 1.0 x 109/L*†
Hemoglobin < 9 g/dL*†
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*
Total bilirubin > 1.5 x ULN, except for patients with documented Gilbert's syndrome who are eligible if total bilirubin ≤ 3 x ULN*
Serum amylase and/or lipase > 1.5 x ULN*
Known or expected hypersensitivity to [177Lu]-NeoB, [68Ga]-NeoB or any of their excipients.
Impaired cardiac function or clinically significant cardiac disease, including any of the following:
Patients with diabetes mellitus not stable under current treatment as judged by the investigator or with hyperglycemia ≥ CTCAE version 5.0 Grade 2*.
Patients with history of or ongoing acute or chronic pancreatitis.
Concurrent bladder outflow obstruction or unmanageable urinary incontinence.
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).
Prior External Beam Radiation Therapy (EBRT) to more than 25% of the bone marrow.
[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).
[Removed]
Patients who have received prior systemic anti-cancer treatment within the following time frames:
History of somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study.
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.
Pregnant or breast-feeding women
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:
True abstinence, when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to IMPs, and withdrawal are not acceptable methods of contraception.
Male or female sterilization. Vasectomised partner is a highly effective birth control method if the partner is the sole sexual partner of the study participant and the vasectomised partner has received medical assessment of the surgical success.
Women tubal ligation is an acceptable highly effective contraception method, but surgical sterility is defined as bilateral salpingectomy (or bilateral oophorectomy or hysterectomy).
Combination of any two of the following (a+b or a+c or b+c):
Sexually active males must use a condom during intercourse while taking the drug and for 4 months after stopping treatment and should not father a child in this period. A condom is required to be used also by vasectomized men in order to prevent delivery of the drug via seminal fluid. Female partners of childbearing potential should use highly effective contraceptive methods during and up to 4 months after stopping treatment.
Use of other investigational drugs within 30 days prior to informed consent signature.
Cohorts A, B, and C: Patient currently receiving NEP inhibitors (e.g., Entresto, racecadotril) and for whom images for dosimetry assessments cannot be acquired.
Cohort E only: Patient meeting at least one of the following conditions
Currently receiving NEP inhibitors (e.g., Entresto, racecadotril)
Known history of angioedema related to previous angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) therapy or hereditary or idiopathic angioedema
Hypersensitivity to the LCZ696 active substances or to any of the excipients
Diabetes mellitus and receiving aliskiren-containing medicinal products
Receiving ACE inhibitors or has discontinued ACE inhibitor therapy within 36 hours before receiving the first dose of LCZ696 in the study
Systolic blood pressure < 100 mmHg¥
Serum potassium level > 5.5 mEq/L¥
To be considered as valid to determine the eligibility of a patient, exam results of exclusion criteria #2, #3, #4, #5, #6, #7, #8, #10 (except LVEF) and #11 must be collected on or after date of patient's informed consent and must be available in the source documents for monitoring. LVEF evaluation is permitted within 6 weeks prior to IMP1 administration, even if performed outside the screening period as part of standard routine clinical practice of care, before ICF signature.
No platelet transfusion, packed red cell transfusion, or G-CSF will be allowed during the selection phase after ICF signature. Transfusion for the sole purpose of making a patient eligible for the study inclusion is not allowed.
Primary purpose
Allocation
Interventional model
Masking
51 participants in 10 patient groups
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Central trial contact
Novartis Pharmaceuticals; Novartis Pharmaceuticals
Data sourced from clinicaltrials.gov
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