Clinical Trial 21664

• Overview

  Study Title:

  Phase 1b/3 z=Global, Randomized, Controlled, Open-Label Trial Comparing Treatment with RYZ101 to Standard of Care (SoC) Therapy in Subjects with Inoperable, Advanced, Somatostatin Receptor Expressing (SSTR+), Well-Differentiated Gastro-Enteropancreatic Neuroendocrine Tumors (GEP-NETs) that have Progressed Following Prior 177Lulabelled Somatostatin Analogue (177Lu-SSA) Therapy (ACTION-1).

  Summary:

  This study aims to determine the safety, pharmacokinetics (PK) and recommended Phase 3 dose (RP3D) of RYZ101 in Part 1, and the safety, efficacy, and PK of RYZ101 compared with investigator-selected standard of care (SoC) therapy in Part 2 in subjects with inoperable, advanced, well-differentiated, somatostatin receptor expressing (SSTR+) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following treatment with Lutetium 177-labelled somatostatin analogue (177Lu-SSA) therapy, such as 177Lu-DOTATATE or 177Lu-DOTATOC (177Lu-DOTATATE/TOC), or 177Lu-high affinity [HA]-DOTATATE.

  Objective:

  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-DOTATATE/177Lu-DOTATOC Part 2 * To determine if treatment with RYZ101, compared to SoC therapy, improves centrally confirmed PFS in study subjects. * To characterize the safety and tolerability of RYZ101 in study subjects

• Treatments

  Therapies:

  Chemotherapy (NOS); Therapy (NOS)

  Medications:

  Amino acids (); Granisetron (); Lanreotide (); Ondansetron (); RYZ101 (); Sunitinib (); Zofran (Ondansetron); everolimus (RAD001); octreotide LAR ()

• Inclusion Criteria

  • Histologically proven, Grade 1-2 well differentiated, inoperable, advanced GEP-NETs (Ki67 > Eastern Cooperative Oncology Group (ECOG) status 0-2
  • Life expectancy of at least 12 weeks
  • Participants with functional tumors who are receiving SSAs on a stable dose for symptom control.
  • Participants that do not require octreotide LAR or lanreotide for symptom control must discontinue SSAs at least 4 weeks prior to enrollment.
  • Progressive, SSTR-PET positive (i.e., Krenning score 3 or 4) GEP-NET (GI or pancreas) based on RECIST v1.1 following 2-4 cycles of treatment with 177Lu-labeled SSA. Must have achieved disease control for at least 3 months following Lu-177 SSA. Premature discontinuation of Lu-177 SSA treatment should not have been due to PD.
  • Part 2: Participant is a candidate for therapy with 1 of the following SoC options:
  • Everolimus 10 mg daily
  • Sunitinib 37.5 mg daily
  • High-dose octreotide LAR 60 mg Q4W
  • High dose frequency lanreotide 120 mg every 2 weeks (Q2W)
  • Adequate renal function, as evidenced by creatinine clearance (CrCl) >50 mL/min
  • Adequate hematologic function, defined by protocol
  • Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 48 hours prior to the first dose of study treatment and agree to use barrier contraception and a second form of highly effective contraception (Clinical Trials Facilitation Group [CTFG] 2014) or total abstinence while receiving study drug and for 6 months following their last dose of RYZ101.
  • Sexually active male subjects must use a condom during intercourse while receiving study drug and for 3 months after the last dose of the study treatment and should not father a child during this period. If sexual partners are WOCBP must also agree to use a second form of highly effective contraception (CTFG 2014) or total abstinence while receiving study drug and for 3 months following their last dose of RYZ101.
  • Able to read and/or understand the details of the study and provide written informed consent prior to any study-specific assessments and procedures commence

• Exclusion Criteria

  • Known hypersensitivity to 225Actinium, 68Gallium, 64Copper, octreotate, or any of the excipients of DOTATATE imaging agents
  • Part 1: Prior treatment with alkylating agents
  • Prior radioembolization
  • Any surgery, chemoembolization, and radiofrequency ablation within 12 weeks prior to first dose of study drug
  • Use of anticancer agents within the following intervals prior to the first dose of study treament:
  • PRRT: within > Chemotherapy: within > Small molecule inhibitors: within > Biological agents: within > Prior external-beam radiation (EBRT) therapy as defined below:
  • Part 1: Any prior EBRT, including SBRT
  • Part 2: Prior EBRT within 6 weeks prior to study enrollment or any prior EBRT to more than 25% of the bone marrow
  • Prior participation in any interventional clinical study within 30 days prior to first dose of study treatment
  • Current somatic or psychiatric disease/condition that may interfere with the objectives and assessments of the study
  • Significant cardiovascular disease, such as New York Heart Association (NYHA) Class ≥II heart failure, left ventricular ejection fraction (LVEF) 450 ms for males and >470 ms for females.
  • Resistant hypertension, defined as uncontrolled blood pressure (BP) >140/90 mmHg while on optimal doses of at least 3 antihypertensive medications with 1 being a diuretic (Whelton et al. 2018)
  • Uncontrolled diabetes mellitus as defined by a fasting glucose >2 x ULN
  • 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.
  • Brain metastases as defined below:
  • Part 1: Known brain metastases
  • Part 2: Subjects with previously treated central nervous system (CNS) metastases who have not recovered from acute side effects of radiotherapy. Note: Subjects with previously treated CNS metastases should be receiving a stable or decreasing dose regimen of steroids
  • Subject requires other treatment that in the opinion of the investigator would be more appropriate than the therapy offered in the study
  • 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
  • Pregnancy or lactation
  • Unable or unwilling to comply with the requirements of the study protocol

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