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244 Prostate Specific Membrane Antigen Antibody Drug Conjugate (PSMA ADC): a Phase 1 Trial in Castration-Resistant Metastatic Prostate Cancer (mCRPC)
Plenary Session 6
Thursday 8 November 2012
Vivo by a Hydrocarbon-Stapled BH3 Helix, Science 2004, 305, 1466– 1470. Bernal, F.; Tyler, A. F.; Korsmeyer, S. J.; Walensky, L. D.; Verdine, G. L. Reactivation of the p53 Tumor Suppressor Pathway by a Stapled p53 Peptide, J. Am. Chem. Soc. 2007, 129, 2456–2457. Moellering, R. E.; Cornejo, M.; Davis, T.; Del Bianco, C.; Aster, J. C.; Blacklow, S. C.; Kung, A. L.; Gilliland, D. G.; Verdine, G. L.; Bradner, J. E. Direct Inhibition of the Notch Transcription Factor Complex, Nature 2009, 462, 182–188.
Thursday 8 November 2012
15:00–16:00
PLENARY SESSION 6
Proffered Paper Session 243 ORAL Phase 1 (Ph1) Clinical and Pharmacodynamic (PD) Study of a Pure MEK Inhibitor (MEKi), RO4987655, in RAS-BRAF Mutant Patient Populations with Advanced or Metastatic Solid Tumors R. Bahleda1 , L. Zimmer2 , M. Martinez Garcia3 , V. Dieras4 , J. Schellens5 , J.P. Spano6 , M.R. Middleton7 , E. Calvo8 , L. Paz Ares9 , F. Barlesi10 . 1 Institut Gustave Roussy, Villejuif Cedex, France; 2 University Hospital Essen, Essen, Germany; 3 Hospital del Mar and Cancer Research Program, Barcelona, Spain; 4 Institut Curie, Paris, France; 5 The Netherlands Cancer ˆ ´ ere, ` La Pitie´ Salpetri Institute, Amsterdam, The Netherlands; 6 Hopital Paris, France; 7 University of Oxford Churchill Hospital, Oxford, United Kingdom; 8 Hospital Universitario Madrid Sanchinarro, Madrid, Spain; 9 Hospital Virgen del Rocio, Sevilla, Spain; 10 Multidisciplinary Oncology and Therapeutic Innovations & CPCET, Marseille, France Background: In the dose-escalation (DE) part of the Ph1 study, RO4987655 showed acceptable and manageable safety profile with linear PK, dose-dependent PD activity (pERK in PBMC) associated with large metabolic FDG-PET response and preliminary antitumor activity at the recommended Ph2 Dose (RP2D). Part II of the study was designed to investigate antitumor and PD activity of RO4987655 as single agent at RP2D dose (8.5 mg bid) in 4 extension cohorts of selected cancer patients with RAS and B-RAF mutations. Patients and Methods: Patients (pts) with melanoma carrying the BRAF V600 mutation (MelV600), melanoma not carrying the BRAF V600 mutation (Mel), Non-Small Cell Lung Cancer (NSCLC) with KRAS mutations, colorectal cancer (CRC) with KRAS and/or BRAF V600 mutations were enrolled to receive oral RO4987655 administered on a continuous twicedaily (8.5 mg bid) in 28 days cycles. PK and full sequential (baseline, C1D15, and C3D1) sampling for PD analysis and somatic mutational profile were implemented (i.e. paired skin and tumor biopsies, blood samples and FDG-PET scans). Results: A total of 95 pts (tumor type, n total/evaluable) (MelV600 n = 18/17, Mel n = 23/20, NSCLC n = 24/18, CRC n= 30/25) were included. Mean age 54.5±12.6 y, previous chemotherapy lines median 2 (0−3). Most common related adverse events included skin (92% of the pts; G3-G4 events reported on 24% of the pts), gastro-intestinal (82%; G3-G4 14%), eye (66%; G3-G4 9%), oedema (51%; G3-G4 5%), CPK increase (34%; G3-G4 17%), fatigue (17%; G3-G4 2%) and metabolic (15%; G3-G4 2%) disorders. PK data were compatible with PK profile in the DE. Efficacy (PR and SD>=16 weeks) was reported in Mel (n = 4 (20%) and n = 4 (20%)), NSCLC (n = 2 (11%) and n = 5 (28%)) but not in CRC (data pending for MelV600). Metabolic PR rate (FDG-PET) was 75%, 70% and 52% in Mel, NSCLC, and CRC, respectively. Statistically significant PD effects were observed in tumor biopsies. Conclusions: RO4987655 showed manageable safety profile comparable to other MEKi. Single agent clinical activity in NSCLC KRAS and Melanoma ‘not BRAF’ (incl. NRAS) was comparable to standard of care in these indications. Evidence of early biological effects and target modulation in tumor was observed in all tumor types despite no clinical activity in KRAS mutated CRC. Across the 4 tumor types, full safety, PK, efficacy data, biomarker analysis and translation to pre-clinical findings will be presented.
75
244 ORAL Prostate Specific Membrane Antigen Antibody Drug Conjugate (PSMA ADC): a Phase 1 Trial in Castration-Resistant Metastatic Prostate Cancer (mCRPC) D. Petrylak1 , P. Kantoff2 , A. Mega3 , J. Stephenson4 , N. Vogelzang5 , M. Fleming6 , S. Blattman7 , N. Stambler7 , P. D’Ambrosio7 , R.J. Israel8 . 1 Columbia University Medical Center, Genitourinary Oncology Section, New York, USA; 2 Dana-Farber Cancer Institute Harvard Medical School, Division of Solid Tumor Oncology, Boston, USA; 3 Brown University, Providence, USA; 4 Cancer Center of the Carolinas, Greenville, USA; 5 Comprehensive Cancer Centers of Nevada/US Oncology Research, Las Vegas, USA; 6 Virginia Oncology Associates, Norfolk, USA; 7 Progenics Pharmaceuticals Inc., Clinical Research, Tarrytown, USA; 8 Progenics Pharmaceuticals Inc., Medical Affairs & Clinical Research, Tarrytown, USA Background: The abundant expression of prostate specific membrane antigen (PSMA) type II transmembrane glycoprotein on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully human antibody to PSMA linked to the potent antitubulin agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage by lysosomal enzymes (Cathepsin B) releases free MMAE, causing cell cycle arrest and apoptosis. We report results from a phase 1 dose escalation study of PSMA ADC in subjects with taxanerefractory mCRPC. Methods: Eligibility requirements included progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Adverse events, pharmacokinetics (PK), PSA, circulating tumor cells, clinical disease progression and immunogenic response to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA and free MMAE was measured by LC/MS/MS. The dosing cohorts range from 0.4 mg/kg to 2.8 mg/kg. Results: 50 subjects have been dosed in nine dose levels (0.4. 0.7, 1.1, 1.6, 1.8, 2.0, 2.2, 2.5, 2.8 mg/kg). PSMA ADC has been generally welltolerated with dose limiting toxicity seen at 2.8 mg/kg being neutropenia (one death) and reversible LFT elevations. Antitumor activity has been manifested as reductions in either PSA or circulating tumor cells in the higher dose cohorts. PSA reductions of ?50% and/or CTC reductions to ?5 cells/7.5 ml blood have been observed in approximately 50% of patients at doses of 1.8 mg/kg. Exposure to PSMA ADC increased with dose and was approximately 1,000-fold greater than MMAE exposure. Similar PK metrics were observed after the first and third doses. Dosing in a 2.5 mg/kg cohort is continuing. Conclusions: PSMA ADC is generally well-tolerated in subjects with mCRPC, previously treated with taxane in doses up to and including 2.5 mg/kg. Antitumor activity in approximately half of the patients at the higher dose levels has been observed. A Phase 2 trial of PSMA ADC in mCRPC is planned. 245 ORAL Towards Prediction of Efficacy of Chemotherapy: a Proof of Concept Study in Lung Cancer Patients Using [11C]docetaxel and Positron Emission Tomography A.A. van der Veldt1 , M. Lubberink2 , R.H. Mathijssen3 , W.J. Loos3 , J. Eriksson2 , A.D. Windhorst1 , N.H. Hendrikse1 , P.E. Postmus4 , E.F. Smit4 , A.A. Lammertsma1 . 1 VU University Medical Center, Nuclear Medicine & PET Research, Amsterdam, The Netherlands; 2 Uppsala University Hospital, PET Centre, Uppsala, Sweden; 3 Erasmus University Medical Center − Daniel den Hoed Cancer Center, Medical Oncology, Rotterdam, The Netherlands; 4 VU University Medical Center, Pulmonology, Amsterdam, The Netherlands Background: Pharmacokinetics of docetaxel can be measured in vivo using positron emission tomography (PET) and carbon-11 labeled docetaxel ([11 C]docetaxel). However, pharmacokinetics of [11 C]docetaxel at tracer doses (microdoses) may be different from those at therapeutic doses. In the current study, the PET microdosing concept was validated for [11 C]docetaxel in lung cancer patients. The objective was to investigate whether a tracer [11 C]docetaxel PET study could predict tumor uptake of (unlabeled) docetaxel during a therapeutic infusion. Patients and Methods: Docetaxel-na¨ıve lung cancer patients underwent two [11 C]docetaxel PET scans; one after bolus injection of [11 C]docetaxel and another during combined infusion of [11 C]docetaxel and a therapeutic dose of docetaxel (75 mg·m−2 ). Each [11 C]docetaxel scan was preceded by a [15 O]water PET scan for measurement of tumor perfusion. During PET scanning, venous samples were collected to measure radioactivity concentrations of [11 C]docetaxel as well as plasma concentrations of docetaxel. Compartmental and spectral analyses were used to quantify
Thursday 8 November 2012
Vivo by a Hydrocarbon-Stapled BH3 Helix, Science 2004, 305, 1466– 1470. Bernal, F.; Tyler, A. F.; Korsmeyer, S. J.; Walensky, L. D.; Verdine, G. L. Reactivation of the p53 Tumor Suppressor Pathway by a Stapled p53 Peptide, J. Am. Chem. Soc. 2007, 129, 2456–2457. Moellering, R. E.; Cornejo, M.; Davis, T.; Del Bianco, C.; Aster, J. C.; Blacklow, S. C.; Kung, A. L.; Gilliland, D. G.; Verdine, G. L.; Bradner, J. E. Direct Inhibition of the Notch Transcription Factor Complex, Nature 2009, 462, 182–188.
Thursday 8 November 2012
15:00–16:00
PLENARY SESSION 6
Proffered Paper Session 243 ORAL Phase 1 (Ph1) Clinical and Pharmacodynamic (PD) Study of a Pure MEK Inhibitor (MEKi), RO4987655, in RAS-BRAF Mutant Patient Populations with Advanced or Metastatic Solid Tumors R. Bahleda1 , L. Zimmer2 , M. Martinez Garcia3 , V. Dieras4 , J. Schellens5 , J.P. Spano6 , M.R. Middleton7 , E. Calvo8 , L. Paz Ares9 , F. Barlesi10 . 1 Institut Gustave Roussy, Villejuif Cedex, France; 2 University Hospital Essen, Essen, Germany; 3 Hospital del Mar and Cancer Research Program, Barcelona, Spain; 4 Institut Curie, Paris, France; 5 The Netherlands Cancer ˆ ´ ere, ` La Pitie´ Salpetri Institute, Amsterdam, The Netherlands; 6 Hopital Paris, France; 7 University of Oxford Churchill Hospital, Oxford, United Kingdom; 8 Hospital Universitario Madrid Sanchinarro, Madrid, Spain; 9 Hospital Virgen del Rocio, Sevilla, Spain; 10 Multidisciplinary Oncology and Therapeutic Innovations & CPCET, Marseille, France Background: In the dose-escalation (DE) part of the Ph1 study, RO4987655 showed acceptable and manageable safety profile with linear PK, dose-dependent PD activity (pERK in PBMC) associated with large metabolic FDG-PET response and preliminary antitumor activity at the recommended Ph2 Dose (RP2D). Part II of the study was designed to investigate antitumor and PD activity of RO4987655 as single agent at RP2D dose (8.5 mg bid) in 4 extension cohorts of selected cancer patients with RAS and B-RAF mutations. Patients and Methods: Patients (pts) with melanoma carrying the BRAF V600 mutation (MelV600), melanoma not carrying the BRAF V600 mutation (Mel), Non-Small Cell Lung Cancer (NSCLC) with KRAS mutations, colorectal cancer (CRC) with KRAS and/or BRAF V600 mutations were enrolled to receive oral RO4987655 administered on a continuous twicedaily (8.5 mg bid) in 28 days cycles. PK and full sequential (baseline, C1D15, and C3D1) sampling for PD analysis and somatic mutational profile were implemented (i.e. paired skin and tumor biopsies, blood samples and FDG-PET scans). Results: A total of 95 pts (tumor type, n total/evaluable) (MelV600 n = 18/17, Mel n = 23/20, NSCLC n = 24/18, CRC n= 30/25) were included. Mean age 54.5±12.6 y, previous chemotherapy lines median 2 (0−3). Most common related adverse events included skin (92% of the pts; G3-G4 events reported on 24% of the pts), gastro-intestinal (82%; G3-G4 14%), eye (66%; G3-G4 9%), oedema (51%; G3-G4 5%), CPK increase (34%; G3-G4 17%), fatigue (17%; G3-G4 2%) and metabolic (15%; G3-G4 2%) disorders. PK data were compatible with PK profile in the DE. Efficacy (PR and SD>=16 weeks) was reported in Mel (n = 4 (20%) and n = 4 (20%)), NSCLC (n = 2 (11%) and n = 5 (28%)) but not in CRC (data pending for MelV600). Metabolic PR rate (FDG-PET) was 75%, 70% and 52% in Mel, NSCLC, and CRC, respectively. Statistically significant PD effects were observed in tumor biopsies. Conclusions: RO4987655 showed manageable safety profile comparable to other MEKi. Single agent clinical activity in NSCLC KRAS and Melanoma ‘not BRAF’ (incl. NRAS) was comparable to standard of care in these indications. Evidence of early biological effects and target modulation in tumor was observed in all tumor types despite no clinical activity in KRAS mutated CRC. Across the 4 tumor types, full safety, PK, efficacy data, biomarker analysis and translation to pre-clinical findings will be presented.
75
244 ORAL Prostate Specific Membrane Antigen Antibody Drug Conjugate (PSMA ADC): a Phase 1 Trial in Castration-Resistant Metastatic Prostate Cancer (mCRPC) D. Petrylak1 , P. Kantoff2 , A. Mega3 , J. Stephenson4 , N. Vogelzang5 , M. Fleming6 , S. Blattman7 , N. Stambler7 , P. D’Ambrosio7 , R.J. Israel8 . 1 Columbia University Medical Center, Genitourinary Oncology Section, New York, USA; 2 Dana-Farber Cancer Institute Harvard Medical School, Division of Solid Tumor Oncology, Boston, USA; 3 Brown University, Providence, USA; 4 Cancer Center of the Carolinas, Greenville, USA; 5 Comprehensive Cancer Centers of Nevada/US Oncology Research, Las Vegas, USA; 6 Virginia Oncology Associates, Norfolk, USA; 7 Progenics Pharmaceuticals Inc., Clinical Research, Tarrytown, USA; 8 Progenics Pharmaceuticals Inc., Medical Affairs & Clinical Research, Tarrytown, USA Background: The abundant expression of prostate specific membrane antigen (PSMA) type II transmembrane glycoprotein on prostate cancer cells provides a rationale for antibody therapy. PSMA ADC, a fully human antibody to PSMA linked to the potent antitubulin agent monomethyl auristatin E (MMAE), binds PSMA and is internalized within the prostate cancer cell where cleavage by lysosomal enzymes (Cathepsin B) releases free MMAE, causing cell cycle arrest and apoptosis. We report results from a phase 1 dose escalation study of PSMA ADC in subjects with taxanerefractory mCRPC. Methods: Eligibility requirements included progressive mCRPC following taxane-containing chemotherapy and ECOG status of 0 or 1. PSMA ADC was administered by IV infusion Q3W for up to 4 cycles. Adverse events, pharmacokinetics (PK), PSA, circulating tumor cells, clinical disease progression and immunogenic response to PSMA ADC were assessed. Serum PSMA ADC and total antibody were measured by ELISA and free MMAE was measured by LC/MS/MS. The dosing cohorts range from 0.4 mg/kg to 2.8 mg/kg. Results: 50 subjects have been dosed in nine dose levels (0.4. 0.7, 1.1, 1.6, 1.8, 2.0, 2.2, 2.5, 2.8 mg/kg). PSMA ADC has been generally welltolerated with dose limiting toxicity seen at 2.8 mg/kg being neutropenia (one death) and reversible LFT elevations. Antitumor activity has been manifested as reductions in either PSA or circulating tumor cells in the higher dose cohorts. PSA reductions of ?50% and/or CTC reductions to ?5 cells/7.5 ml blood have been observed in approximately 50% of patients at doses of 1.8 mg/kg. Exposure to PSMA ADC increased with dose and was approximately 1,000-fold greater than MMAE exposure. Similar PK metrics were observed after the first and third doses. Dosing in a 2.5 mg/kg cohort is continuing. Conclusions: PSMA ADC is generally well-tolerated in subjects with mCRPC, previously treated with taxane in doses up to and including 2.5 mg/kg. Antitumor activity in approximately half of the patients at the higher dose levels has been observed. A Phase 2 trial of PSMA ADC in mCRPC is planned. 245 ORAL Towards Prediction of Efficacy of Chemotherapy: a Proof of Concept Study in Lung Cancer Patients Using [11C]docetaxel and Positron Emission Tomography A.A. van der Veldt1 , M. Lubberink2 , R.H. Mathijssen3 , W.J. Loos3 , J. Eriksson2 , A.D. Windhorst1 , N.H. Hendrikse1 , P.E. Postmus4 , E.F. Smit4 , A.A. Lammertsma1 . 1 VU University Medical Center, Nuclear Medicine & PET Research, Amsterdam, The Netherlands; 2 Uppsala University Hospital, PET Centre, Uppsala, Sweden; 3 Erasmus University Medical Center − Daniel den Hoed Cancer Center, Medical Oncology, Rotterdam, The Netherlands; 4 VU University Medical Center, Pulmonology, Amsterdam, The Netherlands Background: Pharmacokinetics of docetaxel can be measured in vivo using positron emission tomography (PET) and carbon-11 labeled docetaxel ([11 C]docetaxel). However, pharmacokinetics of [11 C]docetaxel at tracer doses (microdoses) may be different from those at therapeutic doses. In the current study, the PET microdosing concept was validated for [11 C]docetaxel in lung cancer patients. The objective was to investigate whether a tracer [11 C]docetaxel PET study could predict tumor uptake of (unlabeled) docetaxel during a therapeutic infusion. Patients and Methods: Docetaxel-na¨ıve lung cancer patients underwent two [11 C]docetaxel PET scans; one after bolus injection of [11 C]docetaxel and another during combined infusion of [11 C]docetaxel and a therapeutic dose of docetaxel (75 mg·m−2 ). Each [11 C]docetaxel scan was preceded by a [15 O]water PET scan for measurement of tumor perfusion. During PET scanning, venous samples were collected to measure radioactivity concentrations of [11 C]docetaxel as well as plasma concentrations of docetaxel. Compartmental and spectral analyses were used to quantify