Clinical Trials /

Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma

NCT03206060

Description:

Background: Pheochromocytoma and paraganglioma are rare tumors. They usually form inside and near the adrenal gland or in the neck region. Not all these tumors can be removed with surgery, and there are no good treatments if the disease has spread. Researchers think a new drug may be able to help. Objective: To learn the safety and tolerability of Lu-177-DOTATATE. Also, to see if it improves the length of time it takes for the cancer to return. Eligibility: Adults who have an inoperable tumor of the study cancer that can be detected with Ga-68-DOTATATE PET/CT imaging Design: Participants will be screened with a medical history, physical exam, and blood tests. Eligible participants will be admitted to the NIH Clinical Center. Participants will get the study drug in an intravenous infusion. They will get 4 doses, given about 8 weeks apart. Between 4 and 24 hours after each study drug dose, participants will have scans taken. They will lie on their back on a scanner table. Participants will have vital signs taken. They will give blood and urine samples. During the study, participants will have other scans taken. Some scans will use a radioactive tracer. Participants will complete quality of life questionnaires. Participants will be contacted by phone 1-3 days after they leave the Clinical Center. They will then be followed every 3 to 6 months for 3 years or until their disease gets worse.

Related Conditions:
  • Adrenal Gland Pheochromocytoma
  • Paraganglioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma
  • Official Title: Lu-177-DOTATATE (Lutathera) in Therapy of Inoperable Pheochromocytoma/ Paraganglioma

Clinical Trial IDs

  • ORG STUDY ID: 170087
  • SECONDARY ID: 17-C-0087
  • NCT ID: NCT03206060

Conditions

  • Pheochromocytoma
  • Paraganglioma
  • Neuroendocrine Tumors
  • Neuroendocrine Neoplasms

Interventions

DrugSynonymsArms
Lu-177-DOTATATE1/Lu-177-DOTATATE
Ga-68-DOTATATE1/Lu-177-DOTATATE
F-18-FDG1/Lu-177-DOTATATE
Amino Acid solution1/Lu-177-DOTATATE

Purpose

Background: Pheochromocytoma and paraganglioma are rare tumors. They usually form inside and near the adrenal gland or in the neck region. Not all these tumors can be removed with surgery, and there are no good treatments if the disease has spread. Researchers think a new drug may be able to help. Objective: To learn the safety and tolerability of Lu-177-DOTATATE. Also, to see if it improves the length of time it takes for the cancer to return. Eligibility: Adults who have an inoperable tumor of the study cancer that can be detected with Ga-68-DOTATATE PET/CT imaging Design: Participants will be screened with a medical history, physical exam, and blood tests. Eligible participants will be admitted to the NIH Clinical Center. Participants will get the study drug in an intravenous infusion. They will get 4 doses, given about 8 weeks apart. Between 4 and 24 hours after each study drug dose, participants will have scans taken. They will lie on their back on a scanner table. Participants will have vital signs taken. They will give blood and urine samples. During the study, participants will have other scans taken. Some scans will use a radioactive tracer. Participants will complete quality of life questionnaires. Participants will be contacted by phone 1-3 days after they leave the Clinical Center. They will then be followed every 3 to 6 months for 3 years or until their disease gets worse.

Detailed Description

      Background:

        -  Pheochromocytomas/paragangliomas (PHEOs/PGLs) are rare tumors arising from neural crest
           tissue that can develop in sympathetic and parasympathetic paraganglia throughout the
           body. Those arising in the adrenal gland are called PHEOs while those located
           extraadrenally are called PGLs.

        -  While benign and uni-focal, PHEO/PGL can be effectively treated with surgical resection,
           patients with metastatic PHEO/PGL often times have few effective and efficient treatment
           options with current treatments aimed more at palliation and symptom control.
           Furthermore, some benign head and neck PGLs may be inoperable because of their size and
           location.

        -  Somatostatin receptors (SSTR), especially type 2, have been shown to be over-expressed
           in a number of human tumors, including gastroenteropancreatic (GEP), carcinoids,
           neuroblastoma, prostate cancer, and PHEO/PGL among many others.

        -  Ionizing radiation such as the beta particles emitted by Lu-177 cause DNA damage to
           target cells through both direct and indirect mechanisms. In addition, ionizing
           radiation has also been shown to induce cell death through what is known as the
           bystander effect, a phenomenon where cellular signaling from irradiated cells towards
           non-irradiated cells induces cellular damage and eventually death in nearby surrounding
           cells.

        -  Lu-177-DOTATATE is a somatostatin analog that predominantly recognizes SSTR2. This
           reagent has been used extensively and its well-tolerated safety profile and efficacy has
           been shown in a variety of neuroendocrine tumors.

      Primary Objective:

      To assess the safety and to evaluate the ability of Lu-177-DOTATATE to improve upon
      progression-free survival (PFS) at 6 months in patients with inoperable, SSTR positive
      PHEO/PGL by comparing PFS of patients treated with Lu-177-DOTATATE to historical controls
      from existing literature.

      Eligibility:

        -  Histologically-proven, surgically inoperable, PHEO/PGL patients (both newly diagnosed or
           patients with existing diagnoses are eligible)

        -  Must have presence of SSTR+ disease as documented by positive Ga-68-DOTATATE PET scan

             -  Positivity of Ga-68-DOTATATE PET scan defined as having at least one lesion that is
                greater than or equal to 10 mm in diameter with uptake that is higher than or equal
                to liver and is qualitatively higher and distinguishable from background activity.

             -  Measurable disease

        -  Age: greater than or equal to 18

        -  Karnofsky Performance Score greater than or equal to 60 or, ECOG Performance Status of 2
           or better

        -  Able to understand and willing to sign informed consent

      Design:

        -  Open-label, single-arm, multi-center, phase 2 study evaluating efficacy and safety of
           Lu-177-DOTATATE in the selected patient population divided into two cohorts: 1) SDHx
           cohort will include patients with the succinate dehydrogenase mutation, which is the
           most common and most aggressive genetic sub-group of patients with PHEO/PGL, and 2)
           apparent sporadic cohort which will include patients without a clear genetic mutation

        -  Simon 2-stage optimal design will be applied to each cohort independently. For each
           cohort, if 11/18 patients are progression-free at 6 months, accrual will proceed to the
           second stage, where an additional 23 patients will be accrued, for a total of 41
           patients per cohort.

        -  Assuming a loss-to-follow-up rate of 10%, a total of 45 patients will be accrued to each
           cohort, with a total accrual ceiling of 90 patients.
    

Trial Arms

NameTypeDescriptionInterventions
1/Lu-177-DOTATATEExperimentalLu-177-DOTATATE is administered IV every 8 (+/- 2) weeks, for a total of 4 administrations. A Ga-68-DOTATATE PET and F-18-FDG-PET, as well as CT/ MRI for RECIST monitoring, will be obtained post 2 administrations and post 4 administrations. Concomitant administration of an IV infusion of an amino acid (AA solution will also be done for renal protection. Concomitant administration of an IV infusion of an amino acid (AA) solution will also be done for renal protection.
  • Lu-177-DOTATATE
  • Ga-68-DOTATATE
  • F-18-FDG
  • Amino Acid solution

Eligibility Criteria

        -  INCLUSION CRITERIA:

               1. Surgically inoperable patients with clinical diagnosis of PHEO/PGL who also have
                  demonstrated disease histologically consistent with pheochromocytoma or
                  paraganglioma (preferably confirmed by research site pathology review if initial
                  pathology was done outside of research site, but not mandatory)

               2. Progressive disease by RECIST with or without symptomswithin the last 12 months
                  Untreated patients with existing histologic diagnoses are eligible if progression
                  can be demonstrated.

               3. PHEO/PGL that is associated with the SDHx mutations or is not associated with any
                  known susceptibility genetic mutations for PHEO/PGL (a.k.a. apparent sporadic ),
                  based on documented genetic testing results obtained prior to study enrollment.
                  PHEO/PGL that is associated with non-SDHx mutations such as VHL, NF1, and RET
                  will not be eligible for this study.

               4. Patient is or will be enrolled on protocol 00-CH-0093, Diagnosis,
                  Pathophysiology, and Molecular Biology of Pheochromocytoma and Paraganglioma (NIH
                  only).

               5. Both metastatic and inoperable primary-only patients are eligible

               6. Must have presence of SSTR+ disease as documented by positive Ga-68-DOTATATE PET
                  scan within 12 weeks of anticipated treatment

                  6.1 Positivity of Ga-68-DOTATATE PET scan defined as having at least one lesion
                  that is greater than or equal to 10 mm in diameter with uptake that is higher
                  than or equal to liver and is qualitatively higher and distinguishable from
                  background activity.

                  6.2 Measurable disease as defined by RECIST 1.1 OR patients with bone-only
                  disease (i.e. no RECIST-measurable lesion) will also be eligible as long as the
                  Ga-68-DOTATATE PET scan is positive

               7. Age greater than or equal to 18

               8. Karnofsky Performance Score greater than or equal to 60 or ECOG Performance
                  Status of 2 or better

               9. Able to understand and willings to sign informed consent

              10. Ability and willingness to obtain all required scans per study schedule.

              11. Negative serum pregnancy test for women of child bearing potential or NOTE: A
                  female is not of childbearing potential if a prior history of hysterectomy with
                  bilateral oophorectomy or other procedure has render the patient surgically
                  sterile, or >2 years since last menstruation.

              12. Female patients of childbearing potential and male patients who are not
                  surgically sterile or with female partners of childbearing potential must agree
                  to use effective, non-hormonal means of contraception (intrauterine contraceptive
                  device, barrier method of contraception in conjunction with spermicidal gel)
                  prior to study entry, for the duration of study participation and for 6 months
                  (10 half-lives of Lu-177) after the last dose of Lu-177- DOTATATE

              13. Must have outside endocrinologist/medical oncologist who can follow the patient
                  after receiving PRRT (NIH only requirement)

              14. Patients with secreting tumors must be receiving adequate pharmacologic
                  catecholamine blockade as determined by the treating physician

              15. Ineligible, unable to or unwilling to receive standard first line therapy for
                  PHEO/PGL

        EXCLUSION CRITERIA:

          1. Creatinine clearance <50 mL/min calculated by the MDRD method, eventually confirmed by
             measured creatinine clearance (or measured glomerular filtration rate (GFR) using
             plasma clearance methods.

          2. Serum albumin less than or equal to 3.0 g/dL unless prothrombin time is within the
             normal range.

          3. Liver dysfunction as evidenced by Child s Class C Liver Disease or worse
             Alternatively, AST or ALT > 2.5 times institutional upper limit of normal (ULN) unless
             liver metastases are present, in which case up to 5 times ULN would be allowed

          4. Hb < 8.0 g/dL; WBC < 2.0 x 10^9/L (or Absolute Neutrophil Count < 1000); Platelets <
             100 x 10^9/L

          5. In patients with symptoms of congestive heart failure, New York Heart Association
             (NYHA) classification of grade III or IV

          6. Pregnancy or lactation

          7. Prior anti-tumoral radionuclide therapy with unsealed sources. Prior therapy with
             sealed radioactive sources such as brachytherapy will be allowed.

          8. Prior local radiation therapy would be allowed as long as there is at least one
             non-irradiated index lesions.

          9. Known brain metastases, unless these metastases have been treated and stabilized for
             at least 24 weeks, prior to enrollment in the study. Patients with a history of brain
             metastases must have a head CT or MRI scan with contrast to document stable disease
             for at least 24 weeks prior to enrolment in the study.

         10. Other known co-existing malignancies except non-melanoma skin cancer and carcinoma in
             situ of the uterine cervix, unless definitively treated and proven no evidence of
             recurrence for 5 years.

         11. Patients who participated in any therapeutic clinical study with an investigational
             agent within the last 30 days.

         12. Patients may be on somatostatin analogue therapy (e.g. but not only limited to
             sandostatin or lanreotide therapy). However, therapy with somatostatin analogues
             should not be initiated or altered within 3 months of study enrolment. Patients on
             short term octreotide may have dose held for 24 hours prior to Lu-177-DOTATATE
             therapy. Those on long acting octreotide therapy will receive treatment at 1 to 5 days
             prior to their next cold octreotide dose, in order to prevent competition for the
             receptor.

         13. Patient weight > 400 lbs (table limit for PET scanner) or per local institutional
             standard for non-NIH sites.

         14. Uncontrolled inter-current illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris,
             hypertension (>180/110), arrhythmia, or psychiatric illness/social situations that
             would limit compliance with study requirements.

         15. Inability to tolerate at least one modality of diagnostic anatomic imaging, such as CT
             or MRI
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:progression-free survival
Time Frame:6 months
Safety Issue:
Description:Median amount of time subject survives without disease progression after treatment

Secondary Outcome Measures

Measure:safety and tolerability profile
Time Frame:30 days after the last dose study drug
Safety Issue:
Description:List of adverse event frequency
Measure:Determine ability to decrease anti-hypertensive medication
Time Frame:3 years
Safety Issue:
Description:Proportion of patients using decreased amount of antihypertensivemedication
Measure:Evaluate Quality of Life
Time Frame:3 years
Safety Issue:
Description:Proportion of patients with increased Quality of Life (QoL)
Measure:Determine changes in plasma biochemical markers
Time Frame:3 years
Safety Issue:
Description:changes in plasma biochemical markers
Measure:Time to tumor progression
Time Frame:at disease progression
Safety Issue:
Description:Median amount of time subject survives without disease progression after treatment
Measure:Objective response rate
Time Frame:at disease progression
Safety Issue:
Description:Proportion of patients whose tumors shrunk after therapy
Measure:Overall survival
Time Frame:at death
Safety Issue:
Description:Median amount of time subject survives after therapy

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Hypertension
  • Catecholamine
  • Familial Syndromes
  • Somatostatin Receptors
  • Ionizing Radiation

Last Updated

January 9, 2020