First in Human (FIH) study to characterize the safety, tolerability, pharmacokinetics (PK), distribution, radiation dosimetry, and anti-tumor activity of [177Lu]-NeoB in patients with advanced solid tumors known to overexpress GRPR and with [68Ga]-NeoB lesion uptake.

This study was designed to establish whether the ligand NeoB, a high affinity antagonist for GRPR, could be used in a theragnostic approach for selection and therapy of GRPRexpressing malignancies: radiolabeled with (1) Gallium 68 (68Ga) to identify lesions and with (2) Lutetium-177 (177Lu) for the treatment of these lesions.

Inclusion Criteria:

• Signed informed consent prior to participation
• Adult patients with advanced solid tumors known to overexpress GRPR
• [68Ga]-NeoB tumor lesion uptake on PET/CT or PET/MRI scan at screening visit (>50% of lesions detected with conventional imaging are identified as well by [68Ga]-NeoB uptake)
• At least one measurable lesion per RECIST 1.1/RANO with a [68Ga]-NeoB uptake
• Patients for whom no standard therapy is available, tolerated or appropriate
• Presence of at least one tumor lesion confirmed with functional or structural imaging (PET, SPECT, CT, MRI, bone scan) within 2 months prior to study entry
• Patient Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.
• Life expectancy more than 6 months.

Exclusion Criteria:

• Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 60 mL/min or serum creatinine > 1.5 x ULN.

• Platelet count of < 75 x 10e9/L

• Absolute neutrophil count (ANC) < 1.0 x 10e9/L

• Hemoglobin < 9 g/dL

• alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x upper limit of normal (ULN) if no demonstrable liver metastases of > 5 x ULN in the presence of liver metastases

• Total bilirubin > 1.5 ULN, except for patients with documented Gilbert's syndrome who are eligible if total bilirubin ≤ x ULN

• Serum amylase and/or lipase > 1.5 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:

  • Clinically significant and/or uncontrolled heart disease such as congestive heart failure requiring treatment (New York Heart Association (NHYA) 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 study entry

• Patients with diabetes mellitus requiring insulin treatment and/or with clinical signs or with fasting plasma glucose > 160 mg/dL (8.9 mmol/L)

• Patients with history of or ongoing acute or chronic pancreatitis

• Prior administration of a radiopharmaceutical with therapeutic intent within a period corresponding to 10 half-lives of the radionuclide used in such radiopharmaceutical

• Prior External Beam Radiation Therapy (EBRT) to more than 25% of the bone marrow

• Patients with a bone scan showing an excessive skeletal radiopharmaceutical uptake with absent or faint activity in soft tissues and the genitourinary tract due to diffuse bone/bone marrow metastases in bone scan also called a "superscan"

• Prior treatment with Radium=223

• Patients who have changed the dose of systemic steroid therapy within less than 2 weeks prior to study entry or patients for whom steroid dose increase is anticipated during the study.

• 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 study treatment
  • Biologic therapy (e.g. antibodies), continuous or intermittent small molecule therapeutics, or any other investigational agents within a period which is ≤ 5T1/2 or ≤ 4 weeks (whichever is longer) prior to study entry

• 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 study 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 6 months after study drug discontinuation. Highly effective contraception methods include:

  • Total abstinence

  • Male or female sterilization

  • Combination of any two of the following (a+b or a+c or b+c)

    1. Use of oral, injected, or implanted hormonal methods of contraception. In case of use of oral contraception, women should be stable on the same pill for a minimum of 3 months before taking study treatment.
    2. Placement of an intrauterine device (IUD) or intrauterine system (IUS).
    3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository. Post-menopausal women are allowed to participate in this study. Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum Follicle-Stimulating Hormone (FSH) levels > 40 mIU/mL [for US only: and estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to screening. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment is she considered not of child bearing potential. Sexually active males must use a condom during intercourse while taking the drug and for 6 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.

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com