Clinical Trials /

Testing the Addition of an Anti-cancer Drug, Triapine, to the Usual Radiation-Based Treatment (Lutetium Lu 177 Dotatate) for Neuroendocrine Tumors

NCT04234568

Description:

This phase I trial studies the side effects and best dose of triapine when given together with lutetium Lu 177 dotatate in treating patients with neuroendocrine tumors. Triapine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radioactive drugs, such as lutetium Lu 177 dotatate, may carry radiation directly to tumor cells and not harm normal cells. Giving triapine and lutetium Lu 177 dotatate together may be a good way in treating patients with neuroendocrine tumors.

Related Conditions:
  • Neuroendocrine Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Addition of an Anti-cancer Drug, Triapine, to the Usual Radiation-Based Treatment (Lutetium Lu 177 Dotatate) for Neuroendocrine Tumors
  • Official Title: A Phase I Trial of Triapine and Lutetium Lu 177 Dotatate in Combination for Well-Differentiated Somatostatin Receptor-Positive Gastroenteropancreatic Neuroendocrine Tumors (GEP-NETs)

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-00170
  • SECONDARY ID: NCI-2020-00170
  • SECONDARY ID: 10388
  • SECONDARY ID: 10388
  • SECONDARY ID: UM1CA186712
  • NCT ID: NCT04234568

Conditions

  • Digestive System Neuroendocrine Tumor
  • Metastatic Well Differentiated Neuroendocrine Neoplasm

Interventions

DrugSynonymsArms
Lutetium Lu 177 Dotatate177 Lu-DOTA-TATE, 177 Lu-DOTA-Tyr3-Octreotate, 177Lu-DOTA0-Tyr3-Octreotate, Lutathera, Lutetium Lu 177 DOTA(0)-Tyr(3)-Octreotate, Lutetium Lu 177-DOTA-Tyr3-Octreotate, lutetium Lu 177-DOTATATE, Lutetium Oxodotreotide Lu-177Treatment (lutetium Lu 177 dotatate, triapine)
Triapine3-aminopyridine-2-carboxaldehyde thiosemicarbazone, 3-AP, 3-Apct, OCX-191Treatment (lutetium Lu 177 dotatate, triapine)

Purpose

This phase I trial studies the side effects and best dose of triapine when given together with lutetium Lu 177 dotatate in treating patients with neuroendocrine tumors. Triapine may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radioactive drugs, such as lutetium Lu 177 dotatate, may carry radiation directly to tumor cells and not harm normal cells. Giving triapine and lutetium Lu 177 dotatate together may be a good way in treating patients with neuroendocrine tumors.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the safety and to determine the recommended phase 2 dose (RP2D) of lutetium Lu
      177 dotatate in combination with triapine.

      SECONDARY OBJECTIVES:

      I. To observe and record anti-tumor activity. II. To determine the overall response rate
      (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at 2, 4, 6, and 8 months
      post therapy.

      III. To measure duration of response (DOR) associated with the combination. IV. To evaluate
      progression-free survival (PFS), 24-month PFS, and overall survival (OS).

      CORRELATIVE OBJECTIVES:

      I. Measure baseline 68 gallium-dotatate biodistribution. II. Evaluate oral triapine plasma
      pharmacokinetics and corresponding methemoglobin level by venous blood gas proportion.

      III. Evaluate NETest at baseline and disease progression to correlate result with clinical
      outcome.

      IV. Describe the tumor molecular profile using whole exome sequencing (WES), as well as
      ribonucleic acid sequencing (RNAseq) by the National Clinical Laboratory Network (NCLN)
      Genomics Lab, and correlate it with treatment outcome.

      V. Collect plasma for circulating deoxyribonucleic acid (DNA) (ctDNA) assessment.

      OUTLINE: This is a dose-escalation study of triapine.

      Patients receive lutetium Lu 177 dotatate intravenously (IV) over 30-40 minutes on day 1 and
      triapine orally (PO) once daily (QD) on days 1-14. Treatment repeats every 8 weeks (56 days)
      for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed every 3 months for 24 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (lutetium Lu 177 dotatate, triapine)ExperimentalPatients receive lutetium Lu 177 dotatate IV over 30-40 minutes on day 1 and triapine PO QD on days 1-14. Treatment repeats every 8 weeks (56 days) for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
  • Lutetium Lu 177 Dotatate
  • Triapine

Eligibility Criteria

        Inclusion Criteria:

          -  Metastatic, histologically confirmed well-differentiated neuroendocrine tumor with
             positive gallium 68 dotatate scan within 6 months. Lesions on gallium 68 dotatate scan
             will be considered positive if the maximum standard uptake value (SUVmax) is > 2 times
             SUV mean of normal liver parenchyma

          -  Failure of at least one prior systemic cancer treatment, including somatostatin
             analogs

          -  Patients must have progressive disease based on RECIST criteria, version 1.1 evidenced
             with computed tomography (CT) scans/magnetic resonance imaging (MRI) obtained within
             24 months from enrollment

          -  Patients must have measurable disease per RECIST 1.1

          -  No prior exposure to peptide receptor radionuclide therapy

          -  Recovered from adverse events of previously administered therapeutic agents to grade 2
             or less toxicity according to Common Terminology Criteria for Adverse Events (CTCAE)
             version 5.0

          -  Archival tissue no longer than 6 months old should be present, otherwise baseline
             research biopsy is needed for WES

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0,1, or 2 (Karnofsky >=
             60%)

          -  Leukocytes >= 2,000/mcL

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 75,000/mcL

          -  Total bilirubin =< 3 x institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3 x institutional ULN

          -  Glomerular filtration rate (GFR) >= 50 mL/min using Cockcroft-Gault method

          -  Hemoglobin >= 8.0 g/dL

          -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
             therapy with undetectable viral load within 6 months are eligible for this trial

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  Patients with treated brain metastases are eligible if follow-up brain imaging after
             central nervous system (CNS)-directed therapy shows no evidence of progression

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen, in the opinion of the enrolling physician, are eligible for
             this trial

          -  Pregnancy precaution: Men and women should avoid pregnancy for seven months after the
             date of their last treatment with lutetium Lu 177 dotatate. It is noteworthy that
             beta-human chorionic gonadotropin (HCG) may be secreted by a small percentage of
             neuroendocrine tumors (NETs), such that, in addition to being a pregnancy marker, it
             also is a tumor marker. Consequently, NET female patients with positive beta-HCG at
             baseline can be eligible to enter the study and receive treatment if pregnancy can be
             excluded by lack of expected doubling of beta-HCG and negative pelvic ultrasound.
             Normally, in pregnant subjects beta-HCG doubles every 2 days during the first 4 weeks
             of pregnancy and every 3.5 days by weeks 6 to 7. Women of childbearing potential
             include any female who has experienced menarche and who has not undergone successful
             surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral
             ovariectomy) or is not postmenopausal (defined as amenorrhea > 12 consecutive months,
             and for women on hormone replacement therapy, only with a documented plasma
             follicle-stimulating hormone [FSH)] level > 35 mIU/mL). Even women who are using oral,
             implanted, or injected contraceptive hormones, an intrauterine device (IUD), or
             barrier methods (diaphragm, condoms, spermicidal) to prevent pregnancy, are practicing
             abstinence or where the partner is sterile (e.g., vasectomy) should be considered to
             be of childbearing potential. Postmenopausal women who have fertilized eggs implanted
             are also considered to be of childbearing potential. Acceptable methods of
             contraception may include total abstinence at the discretion of the Investigator in
             cases where the age, career, lifestyle, or sexual orientation of the patient ensures
             compliance. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
             post-ovulation methods) and withdrawal are not acceptable methods of contraception.
             Reliable contraception (hormonal or barrier method of birth control; abstinence)
             should be maintained throughout the study and for 7 months after study treatment
             discontinuation. All women of childbearing potential and male partners must use a
             double-barrier method of birth control or practice continuous abstinence from
             heterosexual contact throughout the study and for seven months after the end of the
             last treatment

          -  Ability to understand and the willingness to sign a written informed consent document.
             Participants with impaired decision-making capacity (IDMC) who have a
             legally-authorized representative (LAR) and/or family member available will also be
             eligible

        Exclusion Criteria:

          -  Patients who have had major surgical procedures in the prior 6 weeks

          -  Patients with an inability to swallow oral medications or gastrointestinal disease
             limiting absorption of oral agents

          -  Patients who have received prior external beam radiotherapy to more than 50% of bone
             marrow, as determined by a radiation medicine physicist who will calculate the volume
             of bone marrow exposure in prior radiotherapy portals divided by the volume of total
             bone marrow harboring tissues. This ratio must be less than 50 percent

          -  Uncontrolled congestive heart failure (New York Heart Association [NYHA] III, IV)

          -  Patients who have had chemotherapy or radiotherapy within 4 weeks prior to entering
             the study

          -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
             (i.e., have residual toxicities > grade 1) with the exception of alopecia

          -  Patients who are receiving any other investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to triapine or lutetium Lu 177 dotatate

          -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
             or active infection; symptomatic decompensated congestive heart failure; unstable
             angina pectoris; cardiac arrhythmia; and known inadequately controlled hypertension

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant women are excluded from this study because triapine is a ribonucleotide
             reductase (RNR) inhibitor and lutetium Lu 177 dotatate is a peptide receptor
             radionuclide therapy with the potential for teratogenic or abortifacient effects.
             Because there is an unknown but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with triapine and lutetium Lu 177 dotatate,
             breastfeeding should be discontinued if the mother is treated with triapine and
             lutetium Lu 177 dotatate and for 2.5 months following the last treatment

          -  Discontinue long-acting somatostatin analogs (e.g., long-acting octreotide) for at
             least 4 weeks prior to initiating lutetium Lu 177 dotatate. Long-acting somatostatin
             analog will be allowed to continue if patient has history of carcinoid syndrome and
             requires long-acting somatostatin analog for control of his/her functional syndrome
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of triapine
Time Frame:8 weeks (56 days)
Safety Issue:
Description:The MTD will be estimated using isotonic regression based on observed dose limiting toxicity from all patients enrolled in the phase 1 portion and expansion cohort. All patients who received study drugs will be included in the safety analysis.

Secondary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:24 months
Safety Issue:
Description:ORR will be estimated along with 95% exact binomial confidence interval.
Measure:Progression free survival (PFS)
Time Frame:24 months
Safety Issue:
Description:Will be estimated using the Kaplan-Meier curve and median estimates and confidence intervals will be calculated.
Measure:Overall survival
Time Frame:24 months
Safety Issue:
Description:Will be estimated using the Kaplan-Meier curve and median estimates and confidence intervals will be calculated.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

July 10, 2020