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[177Lu]-NeoB in Patients With Advanced Solid Tumors and With [68Ga]-NeoB Lesion Uptake (NeoRay)

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ClinicalTrials.gov Identifier: NCT03872778
Recruitment Status : Recruiting
First Posted : March 13, 2019
Last Update Posted : August 31, 2021
Sponsor:
Information provided by (Responsible Party):
Advanced Accelerator Applications

Brief Summary:
First in Human 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.

Condition or disease Intervention/treatment Phase
Neoplasms Drug: [177Lu]-NeoB Drug: [68Ga]-NeoB Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 86 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Phase I: dose range finding to identify Recommended Phase II Dose Phase IIa: preliminary assessment of anti-tumor activity
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/IIa Open-label, Multi-center Study to Evaluate the Safety, Tolerability, Whole-body Distribution, Radiation Dosimetry and Anti-tumor Activity of [177Lu]-NeoB Administered in Patients With Advanced Solid Tumors Known to Overexpress Gastrin-releasing Peptide Receptor (GRPR)
Actual Study Start Date : July 24, 2019
Estimated Primary Completion Date : August 31, 2023
Estimated Study Completion Date : December 31, 2024

Arm Intervention/treatment
Experimental: Phase I Cohort I

[68 Ga]-NeoB: 50 micrograms/dose at screening

[177Lu]-NeoB: 50 mCi (1.85 GBq) cycle 1, 60% Estimated Cumulative Dose (ECD) for cycles 2-4, q6w

Drug: [177Lu]-NeoB
[177Lu]-NeoB: peptide receptor radionuclide therapy

Drug: [68Ga]-NeoB
[68Ga]-NeoB radioactive diagnostic agent

Experimental: Phase I Cohort II

[68 Ga]-NeoB: 50 micrograms/dose at screening

[177Lu]-NeoB: 60% ECD for 3 cycles (q6w)

Drug: [177Lu]-NeoB
[177Lu]-NeoB: peptide receptor radionuclide therapy

Drug: [68Ga]-NeoB
[68Ga]-NeoB radioactive diagnostic agent

Experimental: Phase I Cohort III

[68 Ga]-NeoB: 50 micrograms/dose at screening

[177Lu]-NeoB: 80% ECD for 3 cycles (q6w)

Drug: [177Lu]-NeoB
[177Lu]-NeoB: peptide receptor radionuclide therapy

Drug: [68Ga]-NeoB
[68Ga]-NeoB radioactive diagnostic agent

Experimental: Phase I Cohort IV

[68 Ga]-NeoB: 50 micrograms/dose at screening

[177Lu]-NeoB: 100% ECD for 3 cycles (q6w)

Drug: [177Lu]-NeoB
[177Lu]-NeoB: peptide receptor radionuclide therapy

Drug: [68Ga]-NeoB
[68Ga]-NeoB radioactive diagnostic agent

Experimental: Phase I Cohort V

[68 Ga]-NeoB: 50 micrograms/dose at screening

[177Lu]-NeoB: 120% ECD for 3 cycles (q6w)

Drug: [177Lu]-NeoB
[177Lu]-NeoB: peptide receptor radionuclide therapy

Drug: [68Ga]-NeoB
[68Ga]-NeoB radioactive diagnostic agent

Experimental: Phase I Cohort VI

[68 Ga]-NeoB: 50 micrograms/dose at screening

[177Lu]-NeoB: 100% ECD for 2 cycles (q6w)

Drug: [177Lu]-NeoB
[177Lu]-NeoB: peptide receptor radionuclide therapy

Drug: [68Ga]-NeoB
[68Ga]-NeoB radioactive diagnostic agent

Experimental: Phase IIa

[68 Ga]-NeoB: 50 micrograms/dose at screening

[177Lu]-NeoB: dose TBD based on Cohorts I-VI, 3 cycles q6w

Drug: [177Lu]-NeoB
[177Lu]-NeoB: peptide receptor radionuclide therapy

Drug: [68Ga]-NeoB
[68Ga]-NeoB radioactive diagnostic agent




Primary Outcome Measures :
  1. Phase I: Incidence of dose limiting toxicities (DLTs) [ Time Frame: 18 months ]
    A dose-limiting toxicity (DLT) is defined as a clinically relevant adverse event or abnormal laboratory value where the relationship to study treatment cannot be ruled out, and which is unrelated to disease, disease progression, intercurrent illness, or concomitant medications that occurs within the DLT monitoring period and meets any of the criteria included in Table 6-3 (Criteria for defining dose-limiting toxicities).

  2. Phase I: Determination of Maximum Tolerated Dose (MTD)/ Recommended phase two dose (RP2D) [ Time Frame: 18 months ]

    The maximum tolerated dose (MTD) and/or the recommended phase II dose (RP2D) of [177Lu]-NeoB will be identified:

    1. MTD is defined as the lowest single dose at which 33% or more of the patients experienced a DLT during the first cycle (6 weeks).
    2. RP2D is defined as the single dose level below the MTD. The number of cycles recommended for Phase II will be defined based on the cumulative dose toxicities reported during Phase I.

  3. Phase IIa: Disease Control Rate (DCR) at week 20 [ Time Frame: Week 20 ]
    DCR is defined as the proportion of patients who have a best overall response of complete response (CR), partial response (PR) or who have stable disease (SD) for >= 20 weeks as assessed by RECIST 1.1 for solid tumors, Response Assessment in Neuro-Oncology (RANO) for glioblastoma indication (GBM).


Secondary Outcome Measures :
  1. Phase I: Tissue Activity Curves (ACs) [ Time Frame: 18 months ]
    Tissue activity curves (ACs) will be 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.

  2. Phase I: Time Activity Curves (ACs) [ Time Frame: 18 months ]
    Time Activity Curves (ACs) describe the percentage of the activity injected versus time.

  3. Phase I: Absorbed radiation doses of [177Lu]-NeoB in critical organs [ Time Frame: 18 months ]
    Absorbed radiation doses in critical organs (e.g. kidneys, bone marrow, pancreas) will be summarized with descriptive statistics. Lesion number will be assigned by dosimetry expert.

  4. Phase I: Urinary excretion of [177Lu]-NeoB [ Time Frame: 18 months ]
    Urine samples will be collected over specified time intervals and analyzed for radioactivity using a gamma counter. The radioactivity excreted in urine will be summarized using descriptive statistics.

  5. Phase I: Half-life of [177Lu]-NeoB in blood [ Time Frame: 18 months ]
    Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. The half-live will be listed and summarized using descriptive statistics.

  6. Phase I: Residence time of [177Lu]-NeoB in organs and tumor lesions [ Time Frame: 18 months ]
    Residence time in organs and tumors lesions will be summarized with descriptive statistics. Lesion number will be assigned by dosimetry expert.

  7. Phase I: Disease Control Rate (DCR) [ Time Frame: 18 months ]
    DCR is defined as the proportion of patients who have a best overall response of complete response (CR), partial response (PR) or who have stable disease (SD) for >= 20 weeks as assessed by RECIST 1.1 for solid tumors, Response Assessment in Neuro-Oncology (RANO) for glioblastoma indication (GBM).

  8. Phase I and Phase IIa: Objective Response Rate (ORR) [ Time Frame: 18 months ]
    ORR is defined as the proportion of participants with Best Overall Response (BOR) of Complete Response (CR) or Partial Response (PR) according to PCWG3 modified RECIST 1.1.

  9. Phase I and Phase IIa: Duration of Response (DOR) [ Time Frame: 18 months ]
    DOR is defined as the duration of time between the date of first documented response (CR or PR) in soft tissue according to PCWG3 modified RECIST 1.1, and the date of first documented progression or death due to any cause.

  10. Phase IIa: Changes from baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) [ Time Frame: 18 months ]
    The QLQ-C30 is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, a global health status / QoL scale, and six single items. Each of the multi-item scales includes a different set of items - no item occurs in more than one scale. All of the scales and single-item measures range in score from 0 to 100. A higher score for the functioning scales and global health status denote a better level of functioning (i.e. a better state of the patient), while higher scores on the symptom and single-item scales indicate a higher level of symptoms (i.e. a worse state of the patient).

  11. Phase IIa: Progression Free Survival (PFS) [ Time Frame: Week 20, Month 6, Month 9 and Month 12 ]
    PFS is defined as the time from date of start of treatment to the date of progression, defined as the first documented progression or death for any cause.

  12. Phase IIa: Overall Survival (OS) [ Time Frame: 18 months ]
    Overall survival (OS) is defined as the time from the date of start of treatment to the date of death due to any cause.

  13. Phase I and Phase IIa: Adverse Events [177Lu]-NeoB [ Time Frame: 18 months ]
    The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

  14. Phase I and Phase IIa: Adverse Events - [68Ga]-NeoB [ Time Frame: 18 months ]
    The distribution of adverse events will be done via the analysis of frequencies for treatment emergent Adverse Event (TEAEs), Serious Adverse Event (TESAEs) and Deaths due to AEs, through the monitoring of relevant clinical and laboratory safety parameters.

  15. Phase I and Phase IIa: Dose interruptions and modifications [ Time Frame: 18 months ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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: breast cancer, lung cancer, prostate cancer, GIST, GBM.
  3. At least one measurable lesion as 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.
  5. Patient Eastern Cooperative Oncology Group (ECOG) performance status =< 2.
  6. Life expectancy more than 6 months.

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) < 60 mL/min or serum creatinine > 1.5 x ULN*
  3. Platelet count of < 75 x 109/L*
  4. Absolute neutrophil count (ANC) < 1.0 x 109/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 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).
  17. Patients who have changed the dose of systemic steroid therapy within less than 2 weeks prior to [177Lu]-NeoB (IMP1) administration or patients for whom steroid dose increase is anticipated during the study.
  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 =< 4 weeks (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 6 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):

    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 [177Lu]-NeoB 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 or bilateral salpingectomy or 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.

  23. Participation in any other investigational trial at the time of informed consent signature.

    • 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 QTcF parameter) and #11 must not be older than 1 month prior to [68Ga]-NeoB administration and must be available in the source documents for monitoring.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03872778


Contacts
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Contact: Novartis Pharmaceuticals 1-888-669-6682 Novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +41613241111 Novartis.email@novartis.com

Locations
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United States, California
City of Hope Recruiting
Duarte, California, United States, 91010
Principal Investigator: Jeffrey YC Wong, MD         
Stanford University Recruiting
Stanford, California, United States, 94305
Principal Investigator: Andrei Iagaru, Dr         
United States, Maryland
John Hopkins University Recruiting
Baltimore, Maryland, United States, 21287
Principal Investigator: Lilja Solnes, MD         
United States, North Carolina
Duke University Recruiting
Durham, North Carolina, United States, 27710
Principal Investigator: Salvador Borges-Neto, MD         
United States, Oregon
Oregon Health & Science University Recruiting
Portland, Oregon, United States, 97239
Principal Investigator: Erick Mittra, Dr         
Austria
Medical University of Innsbruck Recruiting
Innsbruck, Austria
Principal Investigator: Irene Virgolini, MD         
Germany
University of Essen Not yet recruiting
Essen, Germany
Principal Investigator: Herrmann, Pr         
Netherlands
Erasmus MC Recruiting
Rotterdam, Netherlands
Principal Investigator: van der Veldt, Pr         
Spain
Vall d'Hebron Institute of Oncology Not yet recruiting
Barcelona, Spain
United Kingdom
Addenbroke's hospital Not yet recruiting
Cambridge, United Kingdom
Principal Investigator: Aloj, Dr         
Sponsors and Collaborators
Advanced Accelerator Applications
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Advanced Accelerator Applications
ClinicalTrials.gov Identifier: NCT03872778    
Other Study ID Numbers: CAAA603A12101
2018-004727-37 ( EudraCT Number )
First Posted: March 13, 2019    Key Record Dates
Last Update Posted: August 31, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

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


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No