A Pilot, Open-label Study of 18F-Fluciclatide PET/CT Imaging in the Evaluation of Anti-angiogenic Therapy in Solid Tumors

A Pilot, Open-Label, Proof-of-Concept Study of the Use of [18F]Fluciclatide PET/CT Imaging in the Evaluation of Anti-Angiogenic Therapy in Solid Tumors

Background:

• Fluciclatide is a small cyclic peptide containing the RGD tri-peptide, which preferentially binds with high affinity to alpha(v)beta(3) integrins, which are up-regulated in and may regulate angiogenesis.
• [18F]Fluciclatide is a new radiopharmaceutical developed for PET imaging
• Changes in [18F]fluciclatide uptake will be evaluated before and after treatment of patients with targeted antiangiogenic drugs

Objectives:

Primary

• To determine tumor uptake and retention of [18F]fluciclatide before and after 1 cycle of treatment with targeted anti-angiogenic therapy
• Secondary
• To assess the safety of multiple intravenous (IV) administrations of Fluciclatide [18F] Injection in subjects with solid tumors
• To obtain preliminary data on the relationships between [18F]fluciclatide as a pharmacodynamic marker and standard of care imaging markers of clinical response (e.g. contrast-enhanced (CE) static computed tomography (CT), bone scintigraphy, FDG-PET), obtained as part of routine clinical follow-up as specified in the referring protocols, as well as any optional imaging performed

Eligibility:

• Patients greater than or equal to 18 years, with documented malignancy, and solid tumor greater than or equal to 1 cm outside of the liver, who are scheduled to enroll in an NCI therapy protocol using one of the anti-angiogenic agents described in the full protocol
• Platelet count greater than 75,000 x 10(6)/L, hemoglobin greater than 9g/dL, prothrombin time (PT) and aPTT less than 2 times normal limits.
• The subject has not received any targeted anti-angiogenic agents within 60 days prior to pre-treatment (baseline) [18F]fluciclatide administration

Design:

This study is intended to obtain preliminary data on the uptake and retention of [18F]fluciclatide before and after anti-angiogenic therapy. This will enable optimization of the imaging protocol, identification of the most relevant imaging parameters, and allow for calculation of the number patients required to power a larger study to assess the utility of PET imaging with [18F]fluciclatide as a pharmacodynamic biomarker in the context of targeted anti-angiogenic therapies. We expect to enroll 30 evaluable patients in this single center study. Subjects will undergo at least two [18F]fluciclatide PET/CT imaging studies, one pre-therapy and one following completion of 1 cycle of chemotherapy. An optional early post-therapy (2-7 days post therapy commencement) [18F]fluciclatide PET/CT may be performed. The magnitude of [18F]fluciclatide uptake on the pre- and post- treatment PET/CT studies will be evaluated to determine if there is a measureable difference in uptake. Data from the subject's referring therapy protocol will be reviewed for up to one year. An optional DCE-MRI scans of the target lesion may also be performed.

Background:

• Fluciclatide is a small cyclic peptide containing the RGD tri-peptide, which preferentially binds with high affinity to alpha(v)beta(3) integrins, which are up-regulated in and may regulate angiogenesis.
• [18F]Fluciclatide is a new radiopharmaceutical developed for PET imaging
• Changes in [18F]fluciclatide uptake will be evaluated before and after treatment of patients with targeted antiangiogenic drugs

Objectives:

Primary

• To determine tumor uptake and retention of [18F]fluciclatide before and after 1 cycle of treatment with targeted anti-angiogenic therapy
• Secondary
• To assess the safety of multiple intravenous (IV) administrations of Fluciclatide [18F] Injection in subjects with solid tumors
• To obtain preliminary data on the relationships between [18F]fluciclatide as a pharmacodynamic marker and standard of care imaging markers of clinical response (e.g. contrast-enhanced (CE) static computed tomography (CT), bone scintigraphy, FDG-PET), obtained as part of routine clinical follow-up as specified in the referring protocols, as well as any optional imaging performed

Eligibility:

• Patients greater than or equal to 18 years, with documented malignancy, and solid tumor greater than or equal to 1 cm outside of the liver, who are scheduled to enroll in an NCI therapy protocol using one of the anti-angiogenic agents described in the full protocol
• Platelet count greater than 150,000 x 10(6)/L, hemoglobin greater than 9g/dL, prothrombin time (PT) and aPTT less than 2 times normal limits.
• The subject has not received any targeted anti-angiogenic agents within 60 days prior to pre-treatment (baseline) [18F]fluciclatide administration

Design:

This study is intended to obtain preliminary data on the uptake and retention of [18F]fluciclatide before and after anti-angiogenic therapy. This will enable optimization of the imaging protocol, identification of the most relevant imaging parameters, and allow for calculation of the number patients required to power a larger study to assess the utility of PET imaging with [18F]fluciclatide as a pharmacodynamic biomarker in the context of targeted anti-angiogenic therapies. We expect to enroll 30 evaluable patients in this single center study. Subjects will undergo at least two [18F]fluciclatide PET/CT imaging studies, one pre-therapy and one following completion of 1 cycle of chemotherapy. An optional early post-therapy (2-7 days post therapy commencement) [18F]fluciclatide PET/CT may be performed. The magnitude of [18F]fluciclatide uptake on the pre- and post- treatment PET/CT studies will be evaluated to determine if there is a measureable difference in uptake. Data from the subject's referring therapy protocol will be reviewed for up to one year. An optional DCE-MRI scans of the target lesion may also be performed.

• INCLUSION CRITERIA:

• Adult subjects (greater than or equal to18 years old), with documented malignancy, with at least one solid tumor greater than or equal to 1 cm in diameter (not within the liver), who are scheduled to enroll in an NCI therapy protocol using one of the anti-angiogenic therapy agents (Vandetanib, Cediranib or Bevacizumab)

• The subject has a platelet count of 150,000 x 10(6)/L, hemoglobin value of greater than 9 g/dL, PT and an aPTT less than 2 times normal limits.

• The subject has a clinically acceptable medical history, physical examination and vital signs findings during the screening period (from less than 4 weeks before administration of Fluciclatide (18F) Injection); i.e. Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2.

• The subject has had no open surgical wounds in close proximity to the target lesion(s) within 10 days prior to study entry.

• The subject has not had a biopsy of the target lesion within 7 days of PET/CT imaging.

• The subject has not had radiation therapy to the region of the target lesion.

• Enrolling in the following NCI anti-angiogenic therapy protocols:

  08-C-0020

  09-C-0192

  07-C-0058

  09-C-0019

EXCLUSION CRITERIA:

• The subject is pregnant or lactating.
• The subject is being treated with doses of heparin or warfarin resulting in elevation of PT or aPTT greater than 2 times normal.
• The subject has received any anti-angiogenic agent (e.g. bevacizumab, sorafenib, sunitinib) within 60 days prior to pre-treatment (baseline) [18F]fluciclatide PET imaging. This stipulation does not apply after the baseline [18F]fluciclatide PET imaging.
• The subject has received another investigational medicinal product (IMP) within 24 hours before or is scheduled to receive another IMP within 24 hours after Fluciclatide (18F) Injection.
• The subject has any contraindication to any of the study procedures, products used or its constituents (e.g. severe claustrophobia unrelieved by oral anxiolytics).
• The subject is unable to lie still for 75 minutes.
• The subject is known to have a history of hyper- or hypo-coagulation syndromes resulting in prolongation of bleeding parameters. Such coagulopathies include but are not limited to Von Willebrand disease, Protein C deficiency, Protein S deficiency, Hemophilia A/B/C, Factor-V Leiden, and Bernard-Soulier syndrome.
• The subject has undergone a surgical procedure to the target lesion within 28 days prior to baseline [18F]fluciclatide administration OR is scheduled to undergo a surgical procedure between the baseline and post 1-cycle [18F]fluciclatide PET/CT.
• The subject has only bone metastasis

ADDITIONAL INCLUSION CRITERIA FOR SUBJECTS UNDERGOING OPTIONAL MR:

-Serum creatinine within 2 weeks prior to MRI less than or equal to 1.8mg/dl and estimated glomerular filtration rate (eGFR) must be greater than 30 ml/min/1.73m(2).

ADDITIONAL EXCLUSION CRITERIA FOR SUBJECTS UNDERGOING OPTIONAL MR:

• The subject has known allergy to gadolinium

• The subject has contraindications to MRI:

  • Subjects must weigh less than 136 kg (weight limit for scanner table).
  • Subjects cannot have pacemakers, cerebral aneurysm clips, shrapnel injury, or other implanted electronic devices or metal not compatible with MRI.