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Carney ComplexPhase 2NCT01560260

Linsitinib in Treating Patients With Gastrointestinal Stromal Tumors

A Phase 2 study testing Laboratory Biomarker Analysis, Linsitinib and Pharmacological Study in people with Carney Complex and Chondrosarcoma, run by National Cancer Institute (NCI) at 8 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This phase II trial studies how well linsitinib works in treating younger and adult patients with gastrointestinal stromal tumors. Linsitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Laboratory Biomarker Analysis, Linsitinib and Pharmacological Study
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
20 participants
Where
8 sitesUnited States
Study dates
Mar 2012to Oct 2015
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Patients must have histologically confirmed gastrointestinal stromal tumor (GIST) with confirmed genotype of wild-type in a Clinical Laboratory Improvement Amendments (CLIA) certified laboratory
  • Patients will be stratified into pediatric and adult cohorts; patients in the pediatric cohort (age at diagnosis =< 18 years OR diagnosis of Carney Triad or Carney-Stratakis Diad (paraganglioma, pulmonary chondroma) must have received at least sunitinib and have had progression on or intolerance to progression on therapy; patients in the adult cohort (age at diagnosis > 18 years AND no diagnosis of diagnosis of Carney Triad or Carney-Stratakis Diad) have had progression on or intolerance to imatinib therapy as documented by treating physician
  • Performance status: Eastern Cooperative Oncology Group (ECOG) 0-2
  • Patients must have measurable disease defined as lesions that can be measured in 2 dimensions by medical imaging techniques such as CT or magnetic resonance imaging (MRI); ascites, pleural fluid, and lesions seen on PET scan only are not considered measurable
  • White blood cells count (WBC) >= 2.0 x 10^9/L (being >= 14 days off growth factors) OR
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (being >= 14 days off growth factors)
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  • Platelet count >= 75 x 10^9/L
  • Total bilirubin =< 1.5 times the upper limit of normal for age
  • Alanine aminotransferase (ALT)/aspartate aminotransferase (AST) (serum glutamate pyruvate transaminase [SGPT]/serum glutamic oxaloacetic transaminase [SGOT]) =< 3 x the upper limit of normal (ULN) for the reference lab (=< 5 x the ULN for the reference lab in the presence of known hepatic metastasis, adjusted for age)
  • Creatinine clearance > 70 ml/min/1.73m^2 or
  • Serum creatinine < 1.5 x ULN per age and gender
  • QT interval corrected using Frederica formula (QTcF) interval average of < 450 msec at baseline using the Frederica formula (QTcF)
  • No concomitant drugs that prolong the QT corrected (QTc) interval
  • No significant cardiac disease
  • Fasting blood glucose < 150 mg/dL at baseline
  • Hemoglobin A1C (HbA1c) < 7% at screening
  • Patients or their legal representative must be able to read, understand and provide written informed consent to participate in the trial
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; women of childbearing potential must provide a negative pregnancy test (serum or urine) within 7days prior to registration
  • Patients with diabetes mellitus should have controlled disease on oral medications, defined as: no diabetic ketoacidosis (hyperglycemia, ketonuria, pH < 7.3 and bicarbonate < 15mEq/L) at the time of enrollment or within 30 days prior to enrollment and; no change in oral medications greater than 10% within 30 days prior to enrollment
  • Patient must be able to swallow to participate in the study
  • Signed informed consent

Who cannot join

  • Time elapsed from previous therapy must be >= 3 weeks except for prior tyrosine kinase inhibitor therapy which can be >= 7 days; patients must be recovered from the effects of any prior surgery, radiotherapy or systemic therapy
  • Patients who are receiving any other investigational agents or other anti-cancer therapies other than those administered in this study during protocol treatment
  • Patients with diabetes mellitus requiring insulin for control of their diabetes
  • Patients with a history of liver cirrhosis
  • Patients with known brain metastases should be excluded from this clinical trial
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to linsitinib (OSI-906)
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  • While cytochrome P450 1A2 (CYP1A2) inhibitors/inducers are not specifically excluded, investigators should be aware that linsitinib (OSI 906) exposure may be altered by the concomitant administration of these drugs
  • While cytochrome P450 2C9 (CYP2C9) substrates are not specifically excluded, investigators should be aware that levels of drugs metabolized by CYP2C9 may be increased by the concomitant administration of linsitinib (OSI-906); caution should be used when administering CYP2C9 substrates to patients who are on study drug
  • Use of the potent CYP1A2 inhibitors ciprofloxacin and fluvoxamine are prohibited; other less potent CYP1A2 inhibitors/inducers are not excluded
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Prior treatment with another kinase inhibitor targeting insulin-like growth factor 1 receptor (IGF-1R) pathway, including monoclonal antibodies targeting IGF-1R
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with linsitinib (OSI-906)
  • Fertile men and women of childbearing potential not employing an effective method of birth control throughout the trial and for 3 months after last study drug administration in both sexes; women of childbearing potential must have a negative pregnancy test (serum or urine) within the 7 days prior to study drug administration
  • NOTE: Women of childbearing potential include both pre-menopausal women and women within the first 2 years of the onset of menopause
  • NOTE: Effective methods of birth control includes: surgically sterile, barrier device (condom, diaphragm), contraceptive coil, abstinence; oral contraceptive pills (OCPs) alone are not considered an effective method
  • Known human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Use of drugs that have a known risk of causing Torsades de Pointes (TdP) are prohibited within 14 days prior to initiation of linsitinib (OSI-906)
  • Patients with a history of solid organ transplant are ineligible

Trial locations and contacts

8 sites in 1 country.

8 sites in 1 country

United States8 sites

  • Sarcoma Alliance for Research Through Collaboration

    Ann Arbor, Michigan, 48106

  • University of Michigan Comprehensive Cancer Center

    Ann Arbor, Michigan, 48109

  • National Institutes of Health Clinical Center

    Bethesda, Maryland, 20892

  • Dana-Farber/Harvard Cancer Center

    Boston, Massachusetts, 02115

  • University of Iowa/Holden Comprehensive Cancer Center

    Iowa City, Iowa, 52242

  • Stanford Cancer Institute

    Palo Alto, California, 94304

  • Fox Chase Cancer Center

    Philadelphia, Pennsylvania, 19111

  • Oregon Health and Science University

    Portland, Oregon, 97239

Other trials in United States

About this study

Official title: A Phase 2 Study of Linsitinib (OSI-906) in Pediatric and Adult Wild Type Gastrointestinal Stromal Tumors

This phase II trial studies how well linsitinib works in treating younger and adult patients with gastrointestinal stromal tumors. Linsitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the response rate to treatment with OSI-906 (linsitinib) 150mg BID in patients with advanced wild-type (WT) gastrointestinal stromal tumor (GIST).

SECONDARY OBJECTIVES:

  1. To determine the clinical benefit rate (CBR) (stable disease [SD] >= 9 months, partial response [PR], or complete response [CR]) in patients with advanced WT GIST treated with OSI-906.

II. To determine the response duration, progression free survival (PFS), and overall survival (OS) in patients with advanced WT GIST treated with OSI-906.

III. To determine the tolerability and adverse event profile of OSI-906 in patients with advanced GIST.

IV. To explore patterns of protein expression in serum and tumor tissues as predictors of response and progression-free survival (PFS) in advanced WT GIST treated with OSI-906.

  1. To evaluate the metabolic response to OSI-906 using fludeoxyglucose F 18 (FDG)-positron emission tomography (PET).

VI. To determine if tumor metabolic response correlates with anatomic response and clinical benefit.

VII. To measure changes in tumor metabolism by FDG-PET qualitatively and semi-quantitatively with standard uptake value (SUV) and tumor body ratio (TBR) from baseline to first computed tomography (CT)-response evaluation and correlate the findings with size changes as defined by conventional cross-sectional imaging scans.

VIII. To investigate correlations between glucose, insulin, and candidate tumor tissue and blood biomarkers with FDG-PET metabolic response.

OUTLINE:

Patients receive linsitinib orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days, every 12 weeks for 2 years, and then annually thereafter.

Being tested
Laboratory Biomarker Analysis, Linsitinib, Pharmacological Study
Medical subject headings
Carney Complex, Chondrosarcoma, Gastrointestinal Stromal Tumors, Paraganglioma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • LinsitinibDrug

    Also called IGF-1R inhibitor OSI-906, OSI-906, OSI-906AA

    Given PO

  • Pharmacological StudyOther

    Correlative studies

Study groups in NCT01560260
Study groupRoleWhat they receive
Treatment (linsitinib)ExperimentalPatients receive linsitinib 150mg orally (PO) twice daily (BID) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Receives: Other: Laboratory Biomarker Analysis; Drug: Linsitinib; Other: Pharmacological Study

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Complete Response or Partial Response Using Response Evaluation Criteria in Solid Tumors Guideline Version 1.1

    Determine the response rate, Complete Response (CR) or Partial Response (PR), to treatment with linsitinib (OSI-906) in patients with advanced wild-type (WT) gastrointestional stromal tumor (GIST) as determined by RECIST 1.1.

    Measured: At 6 months

Secondary outcomes (10)

  1. Clinical Benefit Rate Defined as Stable Disease (SD) >= 9 Months, Partial Response (PR) or Complete Response (CR)

    Prolonged non-progression is of clinical benefit (CR + PR + SD at 9 months).

    Measured: Up to 2 years

  2. Overall Survival (OS)

    Analyzed using Kaplan-Meier curves for the all treated and per protocol populations.

    Measured: Estimates at 9 months

  3. Progression Free Survival (PFS)

    Analyzed using Kaplan-Meier curves for the all treated and per protocol populations.

    Measured: Time from date of enrollment to time of progression or death due to any cause, estimates at 9 months

  4. Response Duration

    Analyzed using Kaplan-Meier curves for the all treated and per protocol populations.

    Measured: Up to 37 weeks

  5. Failure-free Survival

    Analyzed using Kaplan-Meier curves for the all treated and per protocol populations

    Measured: Up to 37 weeks

  6. Tolerability and Adverse Event Profile of Linsitinib

    To determine the tolerability and adverse event profile of OSI-906 in patients with advanced GIST.

    Measured: Up to 37 weeks

  7. Patterns of Protein Expression in Serum and Tumor Tissues as Predictors of Response and PFS

    To explore patterns of protein expression in serum and tumor tissues as predictors of response and progression-free survival in advanced WT GIST treated with OSI-906. All Insulin Growth Factor Receptor (IGFR) and phosphorylated AKT (pAKT) evaluation was performed in a blinded manner. Distribution and intensity of positive tumor cell staining was assessed for these markers. Loss of succinate dehydrogenase complex flavoprotein subunit A (SDHA) protein expression has been correlated with the presence of a mutation in SDHA. Loss of succinate dehydrogenase complex iron sulfur subunit B (SDHB) protein expression occurs from bi-allelic inactivation of any of the succinate dehydrogenase (SDH) subunit genes. Loss of expression of one member of the complex alters the structure or production of SDH proteins such that the complex is no longer able to form. This results in elevated intracellular levels of succinate as well as loss of demethylase activity.

    Measured: Up to 37 weeks

  8. Number of Participants With Metabolic Response to Linsitinib Using FDG-PET.

    Evaluate the number of participants with metabolic response to OSI-906 using fluorodeoxyglucose positron emission tomography (FDG-PET). Evaluation of metabolic response to linsitinib based on two criteria (EORTC and PERCIST).

    Measured: Up to 37 weeks

  9. Changes in Tumor Metabolism by FDG-PET Qualitatively and Semi-quantitatively With Standard Uptake Value (SUV)

    To measure changes in tumor metabolism by FDG-PET qualitatively and semi-quantitatively with SUV from baseline to first CT response evaluation and correlate the findings with size changes as defined by conventional cross-sectional imaging scans.

    SUVmax determined by: SUVmax = [VOI activity (mCi/ml) * body wt (g)]/injected dose (mCi) SUVpeak determined by identifying the hottest cubic centimeter within a VOI centered on the lesion with the highest FDG.

    Measured: Baseline and 8 weeks

  10. Correlations Between Glucose, Insulin, Tumor Tissue and Blood Biomarkers With FDG-PET Metabolic Response.

    To investigate correlations between glucose, insulin, tumor tissue and blood biomarkers with FDG-PET metabolic response.

    Measured: Up to 37 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted22 Mar 2012 (estimated)
  2. Study startMar 2012
  3. Primary completionOct 2015
  4. Study completionOct 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
20 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01560260
Sponsor's protocol ID
NCI-2012-00708
Other IDs
NCI-2012-00708, CDR0000728619, SARC-022, SARC 022, SARC022, 8945
Status last verified
Aug 2018
First submitted
20 Mar 2012
Last updated
21 Sep 2018

Publications

  • Songdej N, von Mehren M. GIST treatment options after tyrosine kinase inhibitors. Curr Treat Options Oncol. 2014 Sep;15(3):493-506. doi: 10.1007/s11864-014-0295-3.

    PubMed 24952730

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Laboratory Biomarker Analysis, Linsitinib and Pharmacological Study in people with Carney Complex and Chondrosarcoma, run by National Cancer Institute (NCI) at 8 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 21 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 21 Sep 2018. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 19 Jan 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Complete Response or Partial Response Using Response Evaluation Criteria in Solid Tumors Guideline Version 1.1 (time frame: At 6 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01560260, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Sep 2018.

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