Cintredekin Besudotox (IL-13-PE) for Adrenocortical Carcinoma

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2013 by INSYS Therapeutics Inc
Sponsor:
Collaborator:
Information provided by (Responsible Party):
INSYS Therapeutics Inc
ClinicalTrials.gov Identifier:
NCT01832974
First received: September 11, 2012
Last updated: April 12, 2013
Last verified: April 2013
  Purpose

This is an open-label Phase 1/2 study to assess the maximum tolerated dose of cintredekin besudotox (IL-13PE, hlLl3-PE38QQR) and the therapeutic response as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. In Phase 1, patients will first receive a dose of 1 μg/kg intravenously (iv), which if tolerated, will be escalated to a maximum of 3 μg/kg iv. In Phase 2 of the study, patients will receive the maximum tolerated dose determined in Phase 1. The maximum tolerated dose will be administered on Days 1, 3, and 5 of Week 1 of each 4 week cycle for a maximum of 4 cycles (16 weeks). Phase 1 of the study will enroll patients with adrenocortical carcinoma (ACC), malignant pheochromocytoma, pancreatic adenocarcinoma, and hepatocellular carcinoma. Phase 2 of the study will only include patients with ACC.


Condition Intervention Phase
Adrenocortical Carcinoma
Drug: Cintredekin besudotox
Phase 1
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I/II Trial of IL-13-PE in Patients With Treatment Refractory Malignancies With a Focus on Metastatic and Locally Advanced Adrenocortical Carcinoma

Resource links provided by NLM:


Further study details as provided by INSYS Therapeutics Inc:

Primary Outcome Measures:
  • Maximum tolerated dose in Phase 1 of the study [ Time Frame: Phase 1 of the study (up to 5 days) ] [ Designated as safety issue: Yes ]
  • Percentage of participants with an objective response (OR) [ Time Frame: Phase 2 of the study (up to 24 weeks) ] [ Designated as safety issue: No ]
    An OR=a complete (CR) or partial response (PR)/non-CR. All measurable lesions up to a maximum of 5 (maximum of 2/organ) representative of all involved organs will be identified as target lesions (TL) and measured at baseline. A sum of the diameters (SD, longest for non-nodal lesions, short axis for nodal lesions) for all TLs will be calculated and reported as the baseline SD. All other lesions including pathological lymph nodes (LN) will be identified as non-TLs and recorded, but not measured, at baseline. For TLs, CR=disappearance of all TLs and a reduction in the short axis to < 10 mm of any pathological LNs (whether target or non-target), and PR= ≥ 30% decrease in the SD of TLs taking as reference the baseline SD. For non-TLs, CR=disappearance of all non-TLs, normalization of tumor marker level (TML), and all LNs must be non-pathological in size (< 10 mm short axis); and non-CR=the persistence of 1 or more non-TLs and/or maintenance of TML above normal limits.

  • Progression-free survival (PFS) according to Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: Phase 2 of the study (up to 24 weeks) ] [ Designated as safety issue: No ]
    PFS was defined as the time from randomization to disease progression (PD) or death. All measurable lesions (maximum of 5 per organ and 10 in total, those with the longest diameter and suitability for accurate repeated measurements) were identified as target lesions (TL). A sum of the longest diameter for all TLs was calculated and reported as the baseline sum longest diameter(SLD). All other lesions were identified as non-TLs and recorded at baseline. PD for TLs was defined as ≥ 20% increase in the SLD, taking as reference the smallest SLD recorded since treatment started or the appearance of 1 or more new lesions. PD for non-TLs was defined as the appearance of 1 or more new lesions and/or unequivocal progression of existing non-TLs. Patients with neither PD nor death were censored at the date of the last tumor assessment that confirmed no PD. Patients who underwent surgical resection with curative intent without prior progression were censored at the date of surgery.


Estimated Enrollment: 36
Study Start Date: December 2012
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cintredekin besudotox
In Phase 1 of the study, participants will receive cintredekin besudotox 1 μg/kg intravenously (iv) up to a maximum of 3 μg/kg iv. In Phase 2 of the study, participants will receive the maximum tolerated dose iv determined in Phase 1 on Days 1, 3, and 5 of Week 1 of each 4 week cycle for a maximum of 4 cycles (16 weeks).
Drug: Cintredekin besudotox
Phase I of the study will begin with 1 patient who will receive 1 μg/kg. If this patient experiences no greater than grade 1 toxicity of any type, then enrollment of 3-6 patients at the next 2 dose levels, 2 and 3 μg/kg, will start, following a conventional 3+3 design. If the 1 patient at 1 μg/kg experiences any grade 2 or higher toxicity, then enrollment at the 1 μg/kg level will be expanded to a total of 3-6 patients, prior to possible escalation to the 2 and 3 μg/kg dose levels. If none of the first 3 patients experiences a dose-limiting toxicity (DLT) at 1 μg/kg, then escalation will proceed to 2 μg/kg; if 1 patient in the first 3 experiences a DLT at 1 μg/kg, then 3 more will be enrolled at that dose level, with subsequent escalation only if 1/6 has a DLT at 1 μg/kg.
Other Names:
  • IL-13PE
  • hlLl3-PE38QQR

Detailed Description:

The investigators hypothesize that IL-13-PE will cause cancer regression in patients with metastatic and locally advanced adrenocortical carcinoma (ACC) and other malignancies with high IL13Rα2 expression level given the following:

  • High levels of interleukin-13 receptor alpha 2 (IL13Rα2) are observed in ACC and in malignant pheochromocytoma, pancreatic ductal adenocarcinoma, and hepatocellular carcinoma.
  • IL13Rα2 regulates cellular proliferation and invasion of ACC cells.
  • IL-13-PE is highly effective in causing cell death in IL13Rα2 positive ACC cells, and causes tumor regression and prolonged survival in an ACC xenograft nude mice model.

The purposes of this study are:

  • To determine the safety and maximal tolerated dose of IL-13-PE in patients with metastatic and locally advanced ACC and other malignancies with high IL13Rα2 expression level.
  • To determine response rate and progression-free survival in patients with recurrent, metastatic, or primary unresectable ACC treated with IL-13-PE.
  • Evaluate response to IL-13-PE with functional imaging as compared to axial imaging.
  • Determine if response to IL-13-PE treatment is associated with IL13Rα2 expression level.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥18.
  2. Pathological confirmation of adrenocortical carcinoma (ACC) or malignant pheochromocytoma, pancreatic adenocarcinoma, and hepatocellular carcinoma. Tumor positive for IL13Rα2 by immunohistochemistry (≥ 30% of the tumor). Confirmation of tumor positivity will be done at the Laboratory of Pathology, NCI.
  3. Subjects with hepatocellular carcinoma must have a Child-Pugh classification of "A".
  4. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria at presentation.
  5. Patients must have failed standard treatment:

    • Surgical resection, if possible, for ACC and malignant pheochromocytoma.
    • Surgical resection, if possible, for pancreatic adenocarcinoma and hepatocellular carcinoma.
    • Failed at least one FDA approved systemic chemotherapy regimen for pancreatic adenocarcinoma (eg, fluorouracil, erlotinib, gemcitabine, and/or mitomycin) and hepatocellular carcinoma (eg, sorafenib).
  6. Last dose of chemotherapy or last radiotherapy treatment more than 4 weeks prior to starting treatment with this protocol.
  7. Prior or current mitotane therapy is allowed if patients are on the therapy to control hypercortisolemia and have not had a response to the therapy and are tolerating their dose.
  8. No concurrent other investigational therapy.
  9. No currently-active central nervous system (CNS) metastasis; patients may have a history of treated brain metastases.
  10. Life expectancy more than 12 weeks.
  11. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2.
  12. Good organ function, including:

    • Hgb ≥ 8.0 gm/dL; ANC ≥ 1,000/mm^3; platelets ≥ 75,000/mm^3.
    • AST and ALT ≤ 3 x Upper Limit Normal.
    • Bilirubin ≤ Upper Limit Normal.
    • Creatinine clearance > 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal.
  13. No infection requiring parenteral antibiotics.
  14. Sero-negative for HIV antibody.
  15. Sero-negative for Hepatitis B and Hepatitis C.
  16. Not pregnant or nursing. Sexually-active patients must agree to use an effective method of contraception prior to and for 4 months following treatment.
  17. Able to give informed consent.

Exclusion Criteria:

  1. Current coexisting malignancy other than basal cell carcinoma.
  2. Women of child-bearing potential who are pregnant or breastfeeding. Additionally, patients who become pregnant while on study protocol will be discontinued immediately.
  3. Active systemic infections, coagulation disorders, or other major medical illnesses.
  4. Proteinuria ≥ 2+; urinary protein ≥ 1.0 g/24 hours.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01832974

Contacts
Contact: Electron Kebebew, M.D. kebebewe@mail.nih.gov
Contact: Erinn Hopkins 301 496-6457 hopkinsem@mail.nih.gov

Locations
United States, Maryland
NCI/NIH Recruiting
Bethesda, Maryland, United States, 20892
Contact: Electron Kebebew, M.D.       kebebewe@mail.nih.gov   
Sub-Investigator: Krisana Gesuwan, R.N.         
Sub-Investigator: Meenu Jain, Ph.D.         
Sub-Investigator: Naris Nilubol, M.D.         
Sub-Investigator: Mary Ann Toomey, R.N.         
Sub-Investigator: Mei He, M.D.         
Sub-Investigator: Antonio Fojo, M.D., Ph.D.         
Sub-Investigator: Seth Steinberg, Ph.D.         
Sub-Investigator: Raj Puri, M.D.         
Sub-Investigator: Karel Pacak, M.D., Ph.D.         
Sub-Investigator: Constantine Stratakis, M.D., Ph.D.         
Sponsors and Collaborators
INSYS Therapeutics Inc
Investigators
Principal Investigator: Electron Kebebew, M.D. National Institutes of Health (NIH)
  More Information

Publications:
Responsible Party: INSYS Therapeutics Inc
ClinicalTrials.gov Identifier: NCT01832974     History of Changes
Other Study ID Numbers: P11946, 13-C-0046
Study First Received: September 11, 2012
Last Updated: April 12, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by INSYS Therapeutics Inc:
ACC

Additional relevant MeSH terms:
Adrenocortical Carcinoma
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Adrenal Cortex Neoplasms
Adrenal Gland Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Adrenal Cortex Diseases
Adrenal Gland Diseases
Endocrine System Diseases

ClinicalTrials.gov processed this record on July 22, 2014