A first-in-human phase I study of subcutaneous outpatient recombinant human IL15 (rhIL15) in adults with advanced solid tumors

Jeffrey S. Miller, Chihiro Morishima, Douglas G. McNeel, Manish R. Patel, Holbrook E.K. Kohrt, John A. Thompson, Paul M. Sondel, Heather A. Wakelee, Mary L. Disis, Judith C. Kaiser, Martin A. Cheever, Howard Streicher, Steven P. Creekmore, Thomas A. Waldmann, Kevin C. Conlon

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Abstract

Purpose: Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8þ T-cell function, the basis for clinical testing. Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday–Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated. Results: Nineteen patients were treated with rhIL15 at dose levels of 0.25, 0.5, 1, 2, and 3 mcg/kg/day. Fourteen patients completed 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose-limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8þ T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients. Conclusions: SC rhIL15 treatment was well tolerated, producing substantial increases in circulating NK and CD8þ T cells. This protocol establishes a safe outpatient SC rhIL15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with otential as a combination immunotherapeutic agent.

Original languageEnglish (US)
Pages (from-to)1525-1535
Number of pages11
JournalClinical Cancer Research
Volume24
Issue number7
DOIs
StatePublished - Apr 1 2018

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Interleukin-15
Outpatients
Neoplasms
T-Lymphocytes
Troponin
Subcutaneous Injections
Therapeutics
Clinical Protocols
Chest Pain
Renal Cell Carcinoma
Natural Killer Cells
Pancreatitis
Hypotension
Hospitalization
Research Design
Pharmacokinetics
Biomarkers
Injections

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A first-in-human phase I study of subcutaneous outpatient recombinant human IL15 (rhIL15) in adults with advanced solid tumors. / Miller, Jeffrey S.; Morishima, Chihiro; McNeel, Douglas G.; Patel, Manish R.; Kohrt, Holbrook E.K.; Thompson, John A.; Sondel, Paul M.; Wakelee, Heather A.; Disis, Mary L.; Kaiser, Judith C.; Cheever, Martin A.; Streicher, Howard; Creekmore, Steven P.; Waldmann, Thomas A.; Conlon, Kevin C.

In: Clinical Cancer Research, Vol. 24, No. 7, 01.04.2018, p. 1525-1535.

Research output: Contribution to journalArticle

Miller, JS, Morishima, C, McNeel, DG, Patel, MR, Kohrt, HEK, Thompson, JA, Sondel, PM, Wakelee, HA, Disis, ML, Kaiser, JC, Cheever, MA, Streicher, H, Creekmore, SP, Waldmann, TA & Conlon, KC 2018, 'A first-in-human phase I study of subcutaneous outpatient recombinant human IL15 (rhIL15) in adults with advanced solid tumors', Clinical Cancer Research, vol. 24, no. 7, pp. 1525-1535. https://doi.org/10.1158/1078-0432.CCR-17-2451
Miller, Jeffrey S. ; Morishima, Chihiro ; McNeel, Douglas G. ; Patel, Manish R. ; Kohrt, Holbrook E.K. ; Thompson, John A. ; Sondel, Paul M. ; Wakelee, Heather A. ; Disis, Mary L. ; Kaiser, Judith C. ; Cheever, Martin A. ; Streicher, Howard ; Creekmore, Steven P. ; Waldmann, Thomas A. ; Conlon, Kevin C. / A first-in-human phase I study of subcutaneous outpatient recombinant human IL15 (rhIL15) in adults with advanced solid tumors. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 7. pp. 1525-1535.
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abstract = "Purpose: Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8{\th} T-cell function, the basis for clinical testing. Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday–Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated. Results: Nineteen patients were treated with rhIL15 at dose levels of 0.25, 0.5, 1, 2, and 3 mcg/kg/day. Fourteen patients completed 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose-limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8{\th} T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients. Conclusions: SC rhIL15 treatment was well tolerated, producing substantial increases in circulating NK and CD8{\th} T cells. This protocol establishes a safe outpatient SC rhIL15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with otential as a combination immunotherapeutic agent.",
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T1 - A first-in-human phase I study of subcutaneous outpatient recombinant human IL15 (rhIL15) in adults with advanced solid tumors

AU - Miller, Jeffrey S.

AU - Morishima, Chihiro

AU - McNeel, Douglas G.

AU - Patel, Manish R.

AU - Kohrt, Holbrook E.K.

AU - Thompson, John A.

AU - Sondel, Paul M.

AU - Wakelee, Heather A.

AU - Disis, Mary L.

AU - Kaiser, Judith C.

AU - Cheever, Martin A.

AU - Streicher, Howard

AU - Creekmore, Steven P.

AU - Waldmann, Thomas A.

AU - Conlon, Kevin C.

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Purpose: Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8þ T-cell function, the basis for clinical testing. Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday–Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated. Results: Nineteen patients were treated with rhIL15 at dose levels of 0.25, 0.5, 1, 2, and 3 mcg/kg/day. Fourteen patients completed 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose-limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8þ T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients. Conclusions: SC rhIL15 treatment was well tolerated, producing substantial increases in circulating NK and CD8þ T cells. This protocol establishes a safe outpatient SC rhIL15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with otential as a combination immunotherapeutic agent.

AB - Purpose: Preclinical data established IL15 as a homeostatic factor and powerful stimulator of NK and CD8þ T-cell function, the basis for clinical testing. Experimental Design: A first-in-human outpatient phase I dose escalation trial of subcutaneous (SC) rhIL15 was conducted in refractory solid tumor cancer patients. Therapy consisted of daily (Monday–Friday) subcutaneous injections of rhIL15 for two consecutive weeks (10 total doses/cycle). Clinical response was assessed by RECIST. Pharmacokinetics of rhIL15 and immune biomarkers were evaluated. Results: Nineteen patients were treated with rhIL15 at dose levels of 0.25, 0.5, 1, 2, and 3 mcg/kg/day. Fourteen patients completed 2 cycles of therapy that was well tolerated. One serious adverse event (SAE), grade 2 pancreatitis, required overnight hospitalization. Enrollment was halted after a patient receiving 3 mcg/kg/day developed a dose-limiting SAE of grade 3 cardiac chest pain associated with hypotension and increased troponin. No objective responses were observed; however, several patients had disease stabilization including a renal cell carcinoma patient who continued protocol treatment for 2 years. The treatment induced profound expansion of circulating NK cells, especially among the CD56bright subset. A proportional but less dramatic increase was found among circulating CD8þ T cells with maximal 3-fold expansion for the 2 and 3 mcg/kg patients. Conclusions: SC rhIL15 treatment was well tolerated, producing substantial increases in circulating NK and CD8þ T cells. This protocol establishes a safe outpatient SC rhIL15 regimen of 2 mcg/kg/day dosing amenable to self-injection and with otential as a combination immunotherapeutic agent.

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