IMC-A12 With Mitotane vs Mitotane Alone in Recurrent, Metastatic, or Primary ACC That Cannot Be Removed by Surgery

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Brief Title

IMC-A12 With Mitotane vs Mitotane Alone in Recurrent, Metastatic, or Primary ACC That Cannot Be Removed by Surgery

Official Title

Multi-Institutional Phase II Study of IMC-A12, a Recombinant Human IgG1 Monoclonal Antibody Directed at the Type I Insulin-Like Growth Factor Receptor IGF1R, in Adrenocortical Carcinoma: IMC-A12 With Mitotane vs Mitotane Alone

Brief Summary

      This randomized phase II trial is studying mitotane and IMC-A12 to see how well they work
      compared with mitotane alone in treating patients with recurrent, metastatic, or primary
      adrenocortical cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as
      mitotane, work in different ways to stop the growth of tumor cells, either by killing the
      cells or by stopping them from dividing. Monoclonal antibodies, such as IMC-A12, can block
      tumor growth in different ways. Some block the ability of tumor cells to grow and spread.
      Others find tumor cells and help kill them or carry tumor-killing substances to them. It is
      not yet known whether mitotane is more effective with or without monoclonal antibody IMC-A12
      in treating adrenocortical cancer.
    

Detailed Description

      PRIMARY OBJECTIVES:

      I. Compare the progression-free survival (PFS) rate in patients with recurrent, metastatic,
      or primary unresectable adrenocortical carcinoma treated with mitotane with vs without
      anti-IGF-1R recombinant monoclonal antibody IMC-A12 (IMC-A12).

      SECONDARY OBJECTIVES:

      I. Compare the response rates in these patients using Response Evaluation Criteria in Solid
      Tumor (RECIST) criteria.

      II. Compare the change in tumor size from baseline to 12 weeks in these patients.

      III. Compare the overall trajectories in tumor growth in these patients.

      TERTIARY OBJECTIVES:

      I. Define predictive markers of response or insensitivity to IMC-A12. II. Define
      pharmacodynamic markers of IMC-A12. III. Determine whether tumor expression of IGF-IR and
      activation of downstream signaling in archival tumor tissue samples predict efficacy of
      IMC-A12.

      OUTLINE: This is a multicenter study that includes a single-arm safety evaluation phase
      followed by a randomized phase. Initially, patients are enrolled in the safety evaluation
      phase. If ≤ 6 of 20 patients experience a dose-limiting toxicity, then the study may proceed
      to the randomized phase.

      SAFETY EVALUATION PHASE: Patients receive oral mitotane once or twice daily and anti-IGF-1R
      recombinant monoclonal antibody IMC-A12 IV over 1 hour once every 2 weeks in the absence of
      disease progression or unacceptable toxicity.

      RANDOMIZED PHASE: Patients are stratified according to participating center. Patients are
      randomized to 1 of 2 treatment arms.

      ARM I: Patients receive oral mitotane once or twice daily in the absence of disease
      progression or unacceptable toxicity. Patients with documented disease progression may cross
      over and receive treatment on arm II.

      ARM II: Patients receive mitotane as in arm I and anti-IGF-1R recombinant monoclonal antibody
      IMC-A12 IV over 1 hour once every 2 weeks in the absence of disease progression or
      unacceptable toxicity.

      Archival frozen tissue blocks, unstained tumor tissue slides from archival paraffin blocks,
      plasma samples, and urine samples may be collected and stored for future correlative
      biomarker studies.

      After completion of study therapy, patients are followed up for 6 months.

      NOTE: The study was terminated after the safety evaluation phase (i.e., before the
      randomization phase) due to futility concerns. Thus, patients were only enrolled into ARM II
      (i.e., mitotate + IMC-A12). Results presented in this report are only given for the safety
      evaluation phase.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Progression-free Survival Rate at 6 Weeks

Secondary Outcome

 Best Response Rates

Condition

Recurrent Adrenocortical Carcinoma

Intervention

IMC-A12

Study Arms / Comparison Groups

 Arm II (Mitotane + IMC-A12)
Description:  Patients receive mitotane as in arm I and anti-IGF-1R recombinant monoclonal antibody IMC-A12 IV over 1 hour once every 2 weeks in the absence of disease progression or unacceptable toxicity.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

20

Start Date

December 2008

Completion Date

March 2014

Primary Completion Date

May 2012

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed adrenocortical carcinoma

               -  Documented unresectable recurrent, unresectable advanced, or metastatic disease

          -  At least 1 lesion that can be accurately measured by RECIST criteria as ≥ 20 mm by
             conventional radiologic techniques or as ≥ 10 mm by spiral CT scan or MRI

               -  Patients with disease in an irradiated field as the only site of measurable
                  disease allowed provided there has been a clear progression of the lesion

          -  No tumors potentially resectable by surgical excision alone

          -  No known or suspected leptomeningeal disease or brain metastases

          -  ECOG performance status 0-2

          -  Life expectancy ≥ 12 weeks

          -  ANC ≥ 1,500/mm^3

          -  Platelet count ≥ 100,000/mm^3

          -  Hemoglobin ≥ 9 g/dL (transfusion allowed)

          -  Serum creatinine ≤ 1.5 times upper limit of normal (ULN) OR calculated creatinine
             clearance ≥ 60 mL/min

          -  AST or ALT ≤ 3 times ULN

          -  Total bilirubin ≤ 1.5 times ULN

          -  HbA1c < 8 within the past 4 weeks

          -  Not pregnant or nursing

          -  Negative pregnancy test

          -  Fertile patients must use effective contraception during and for 3 months after
             completion of study therapy

          -  Able to take oral medications

          -  No poor gastrointestinal absorption

          -  Patients with diabetes mellitus are eligible provided they meet all of the following
             criteria:

               -  Blood glucose is normal (random glucose ≤ 150 mg/dL)

               -  HgbA1c ≤ 8 within the past 4 weeks

               -  On a stable dietary or therapeutic regimen for the past 2 months

          -  No active uncontrolled infection

          -  No severe disease or condition that, in the judgement of the investigator, would make
             the patient inappropriate for study participation, including, but not limited to:

               -  Bleeding diathesis

               -  Uncontrolled chronic kidney or liver disease

               -  Uncontrolled diabetes

               -  History of cardiac history

               -  Myocardial infarction within the past 6 months

               -  Congestive heart failure

               -  Unstable angina pectoris

               -  Cardiac arrhythmia

               -  Uncontrolled hypertension

          -  No current malignancy or previous malignancy with a disease-free interval of < 2 years
             at the time of diagnosis

               -  Patients with adequately treated basal cell or squamous cell carcinoma of the
                  skin, carcinoma in situ of the cervix or skin, or stage A low-grade prostate
                  cancer are eligible

          -  No known hypersensitivity to monoclonal antibody therapy or mitotane

          -  No known HIV or hepatitis B or C infection

          -  No serious medical or psychiatric disorder that would interfere with patient safety or
             informed consent

          -  All significant toxic effects of prior surgery resolved to ≤ grade 1 according to NCI
             CTCAE v. 3.0 criteria

          -  Mitotane for < 8 weeks prior to study entry AND tolerated it well

          -  No prior IGFR-directed therapy

          -  No prior systemic antitumor therapy (cytotoxic chemotherapy, biologic, immunotherapy,
             or targeted therapy)

               -  Prior incomplete surgical resections or radiofrequency ablation or radiotherapy
                  will not be considered as prior therapy provided measurable sites of disease
                  remain

               -  Prior adjuvant chemotherapy or mitotane will not be considered as prior antitumor
                  therapy unless it was completed < 6 months before study enrollment

          -  No prior radiotherapy to > 20% of bone marrow

          -  More than 4 weeks since prior and no concurrent radiotherapy

               -  Radiotherapy for palliation of symptoms related to metastases is permitted
                  provided that it is > 4 weeks from study initiation, and does not involve
                  target/measureable lesions that are followed for drug treatment response
                  evaluation

          -  No concurrent mitotane ≥ 8 weeks prior to study

          -  No concurrent tumor resection or tumor-directed surgery

          -  No other concurrent anticancer or investigational therapy
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Gary Hammer, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00778817

Organization ID

NCI-2009-00291

Secondary IDs

NCI-2009-00291

Responsible Party

Sponsor

Study Sponsor

National Cancer Institute (NCI)


Study Sponsor

Gary Hammer, Principal Investigator, University of Chicago Comprehensive Cancer Center


Verification Date

December 2013