| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| gastro-enteropancreatic neuroendocrine tumors (GEP-NETs) |
|
| E.1.1.1 | Medical condition in easily understood language |
| gastro-enteropancreatic neuroendocrine tumors (GEP-NETs) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10077559 |
| E.1.2 | Term | Gastroenteropancreatic neuroendocrine tumour disease |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10077560 |
| E.1.2 | Term | Gastroenteropancreatic neuroendocrine tumor disease |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Part 1:
- To determine the RP3D of RYZ101
- To assess the safety and tolerability of RYZ101 in subjects with SSTR+ GEP-NET that has progressed following treatment with 177Lu-SSA
Part 2:
- To determine if treatment with RYZ101, compared to SoC therapy, improves centrally confirmed PFS in study subjects. |
|
| E.2.2 | Secondary objectives of the trial |
Part 2:
- To determine if treatment with RYZ101, compared to SoC therapy, improves OS in study subjects.
- To determine if treatment with RYZ101, compared to SoC therapy, improves ORR in study subjects
- To evaluate the efficacy of RYZ101 compared to SoC therapy in terms of Investigator-assessed PFS
- To further evaluate the efficacy of RYZ101 compared to SoC therapy by Investigator-assessed ORR, as well as BOR, DoR, and disease control rate as determined by BICR and by the Investigator.
- To characterize the safety and tolerability of RYZ101 in study subjects
- To evaluate the PK of RYZ101
- To evaluate PK and ECG parameters in a subset of approximately 30 subjects |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| A PK and ECG substudy will be conducted in a subset of approximately 30 subjects randomized to RYZ101 in Part 2 at select sites |
|
| E.3 | Principal inclusion criteria |
1. Histologically proven, Grade 1-2 well differentiated, inoperable, advanced GEP-NETs.
2. Ki67 (mitotic) index ≤20%.
3. Eastern Cooperative Oncology Group (ECOG) status 0-2.
4. Life expectancy of at least 12 weeks.
5. Subjects with functional tumors who are receiving octreotide LAR or lanreotide for symptom control must be on a stable dose for at least 12 weeks prior to enrollment (Part 1) or randomization (Part 2).
a. Subjects with nonfunctional tumors or functional tumors that do not require octreotide LAR or lanreotide for symptom control must discontinue octreotide LAR or lanreotide at least 4 weeks prior to enrollment (Part 1) or randomization (Part 2).
6. Progressive GEP-NET (GI or pancreas) based on RECIST v1.1 following a minimum of 2 cycles and a maximum of 4 cycles of treatment with 177Lu-DOTATATE (7.4 GBq ±10% each cycle), 177Lu-DOTATOC (7.5 GBq ±10% each cycle), or 177Lu-HA-DOTATATE (7.4 GBq ±10% each cycle). Premature discontinuation of 177Lu-DOTATATE, 177Lu-DOTATOC, or 177Lu-HA-DOTATATE treatment should not have been due to PD. Dose reductions for toxicity based on local labeling are allowed.
a. CT/MRI scan should be completed within 4 weeks prior to enrollment (Part 1) or randomization (Part 2) and show disease progression compared to the scan demonstrating disease control (CR, PR, or SD) following the last 177Lu-DOTATATE/TOC or 177Lu-HA-DOTATATE treatment (see Exclusion Criterion #1). Disease progression must be centrally confirmed prior to randomization (Part 2).
b. For subjects on octreotide LAR or lanreotide, progression should be documented while the subject was on a fixed dose of octreotide LAR or lanreotide.
c. There must be at least 1 SSTR-PET imaging-positive (using a regulatory agency-approved imaging method, e.g., 68Gallium [68Ga] or 64Copper [64Cu]-based), measurable site of disease (according to RECIST v1.1) and no RECIST v1.1 measurable metastatic lesions that are SSTR imaging -negative. Assessment of SSTR expression must be within 3 months prior to enrollment (Part 1) or randomization (Part 2) without any intervening non-SSA anticancer treatments for GEP-NET.
d. Tumor uptake observed in each RECIST v1.1 measurable lesion using a regulatory agency -approved SSTR-PET imaging method must be greater than the liver uptake observed on regulatory agency-approved SSTR-PET imaging, to be centrally confirmed in Part 2.
7. Part 2: Subject is a candidate for therapy with 1 of the following SoC options:
a. Everolimus 10 mg daily by mouth
b. Sunitinib 37.5 mg daily by mouth
c. High-dose octreotide LAR 60 mg Q4W by intramuscular (i.m.) injection
d. High dose frequency lanreotide 120 mg every 2 weeks (Q2W) by deep subcutaneous (s.c.) injection.
8. Adequate renal function, as evidenced by creatinine clearance (CrCl) ≥60 mL/min (calculated using the Cockcroft-Gault formula)
9. Adequate hematologic function, defined by the following laboratory results:
a. Part 1: Hemoglobin concentration ≥5.6 mmol/L (≥9.0 g/dL); absolute neutrophil count (ANC) ≥1500 cells/µL (≥1500 cells/mm3); platelets ≥100 x 109/L (100 x 103/mm3)
b. Part 2: Hemoglobin concentration ≥5.0 mmol/L (≥8.0 g/dL); ANC ≥1000 cells/µL (≥1000 cells/mm3); platelets >100 x 109/L (100 x 103/mm3).
10. Total bilirubin ≤3 x upper limit normal (ULN)
11. Serum albumin ≥3.0 g/dL unless prothrombin time (PT) is within the normal range
12. For women of childbearing potential (WOCBP):
a. Negative serum pregnancy test within 48 hours prior to the first dose of study treatment
b. Agreement to use barrier contraception and a second form of highly effective contraception while receiving study treatment and for 6 months following their last dose of study treatment. Alternatively, total abstinence is also considered a highly effective contraception method when this is in line with the preferred and usual lifestyle of the subject.
c. A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (total hysterectomy, or bilateral tubal ligation or bilateral oophorectomy at least 6 weeks before taking study treatment).
13. Sexually active male subjects must use a condom during intercourse while receiving study treatment and for 3 months after the last dose of the study treatment and should not father a child during this period.
a. Male study participants whose sexual partners are WOCBP must also agree to use a second form of highly effective contraception while receiving study treatment and for 3 months following their last dose of RYZ101. Alternatively, total abstinence is also considered a highly effective contraception method.
b. A condom is required to be used also by vasectomized men as well as during intercourse with a male partner to prevent delivery of the drug via seminal fluid. |
|
| E.4 | Principal exclusion criteria |
1. Subjects with a GEP-NET deemed nonresponsive to PRRT, defined as no disease control (PR, CR, or SD) achieved for at least 6 months following the last dose of prior 177Lu-DOTATATE/TOC or 177Lu-HA-DOTATATE treatment.
2. Known hypersensitivity to 225Actinium, 68Gallium, 64Copper, octreotate, or any of the excipients of DOTATATE imaging agents
3. Part 1: Prior treatment with alkylating agents
4. Prior radioembolization
5. Any surgery, chemoembolization, and radiofrequency ablation within 12 weeks prior to first dose of study treatment
6. Use of anticancer agents within the following intervals prior to the first dose of study treatment:
a. PRRT: within < 6 months (PRRT other than 177Lu-DOTATATE/TOC or 177Lu-HA-DOTATATE only, as described in Inclusion Criterion #7 is excluded)
b. Chemotherapy: within <6 weeks
c. Small molecule inhibitors: within <4 weeks
d. Biological agents: within 4 weeks
7. Prior radiation therapy as defined below:
a. Part 1: Any prior external beam radiation therapy, including stereotactic body radiation therapy (SBRT)
b. Part 2: Any of the following:
i. Radiation therapy within 6 weeks prior to study enrollment
ii. Prior external beam radiation therapy to more than 25% of the bone marrow
8. Prior participation in any interventional clinical study within 30 days prior to first dose of study treatment
9. Current somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
10. Significant cardiovascular disease, such as New York Heart Association (NYHA) Class ≥II heart failure
a. Subjects with a known left ventricular ejection fraction (LVEF) <40% will be excluded.
b. Subjects with known coronary artery disease, congestive heart failure not meeting the above criteria, or LVEF <50% must be on a stable medical regimen that is optimized in the opinion of the treating physician.
c. QT interval corrected for heart rate using Fridericia’s formula (QTcF) >470 ms for females and >450 ms for males, demonstrated by the average value of 3 consecutive ECGs
11. Resistant hypertension, defined as persistent uncontrolled blood pressure (BP) >140/90 mmHg while on optimal doses of at least 3 antihypertensive medications with 1 being a diuretic. Patients with baseline hypertension may be eligible after initiation of antihypertensive therapy.
12. Uncontrolled diabetes mellitus as defined by hemoglobin A1C (HgB A1C) ≥8%
13. Have a history of primary malignancy within the past 3 years other than (1) GEP-NET, (2) adequately treated carcinoma in situ or non-melanoma carcinoma of the skin, (3) any other curatively treated malignancy that is not expected to require treatment for recurrence during participation in the study, or (4) an untreated cancer on active surveillance that may not affect the subject’s survival status for ≥3 years based on clinician assessment/statement and with Medical Monitor approval.
14. Known brain, meningeal or spinal cord metastases. In Part 2, subjects with previously treated brain metastases will be allowed if the following conditions are met: (a) there is no evidence
of central nervous system (CNS) progression for at least 6 months as assessed by local MRI for brain metastasis during screening; (b) the subject has recovered from acute side effects of
radiotherapy; and (c) the subject is receiving a stable or decreasing dose of steroids.
15. For subjects with functional tumors that require treatment with SSAs for symptom control:
a. Any subject receiving treatment with short-acting octreotide, which cannot be interrupted for 24 hours before the administration of RYZ101.
b. Any subject receiving treatment with octreotide LAR or lanreotide, which cannot be interrupted for at least 4 weeks before the administration of RYZ101.
16. Subject requires other treatment that in the opinion of the investigator would be more appropriate than the therapy offered in the study
18. Unable or unwilling to comply with the requirements of the study protocol
19. PRRT other than 177Lu-DOTATATE/TOC or 177Lu-HA-DOTATATE as described in Inclusion Criterion #7
20. Any condition requiring systemic treatment with high-dose glucocorticoids (≥20 mg prednisone per day or equivalent) within 14 days prior to first dose of study treatment and/or which cannot be stopped while on study (unless solely for the purpose of adrenal replacement). Inhaled or topical steroids and single dose of steroids as pre-medication for CT scans with contrast are permitted.
21. Any history of liver cirrhosis. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1:
- Rate Incidence of DLTs during the first 56 days of study treatment
- Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings
Part 2:
- PFS as determined by BICR
PFS will be defined as the time from the date of randomization until the date of progression (as determined by BICR from tumor assessments using RECIST v1.1) or death due to any cause, whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| after the target number of 197 PFS events have occurred. |
|
| E.5.2 | Secondary end point(s) |
Part 2:
- OS
OS will be defined as the time from the date of randomization until the date of death due to any cause.
- ORR, as determined by BICR according to RECIST v1.1
- PFS as determined by the Investigator
- ORR, as assessed by the Investigator according to RECIST v1.1
- BOR, disease control rate (PR + CR + SD), and DoR (only for subjects with a RECIST v1.1 response) assessed by BICR and by the Investigator according to RECIST v1.1
- Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings
- PFS2 as determined by the investigator
PFS2 will be defined as the time from randomization to second objective disease progression after subsequent anti-cancer therapy, or death from any cause, whichever first.
- Relationship between biomarkers, including but not limited to CgA in the serum and (5 HIAA) in the urine, with AEs of special interest and/or efficacy endpoints (e.g., PFS, OS, BOR, DoR)
- Changes in:
•EQ-5D-5L
•EORTC QLQ-C30 and
•EORTC QLQ GI NET21 questionnaire scores.
- Population predicted exposure parameters (i.e. Cmax, AUC, average concentration)
- Relationship between exposure endpoints and clinical outcomes (efficacy and safety)
- PK parameters, measured by:
• Cmax, Tmax, AUC, Vd, clearance, T1/2
• Percentage of radioactivity of the injected parent drug recovered in urine
• ECG parameters (including QTc), measured by continuous ECG recording using a 12 lead Holter monitoring device
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Up to 80 months or until a total of 133 deaths have occurred, whichever occurs first
- Up to 80 months |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 23 |
| 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 |
| Brazil |
| Canada |
| Korea, Republic of |
| United States |
| Belgium |
| France |
| Netherlands |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 9 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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