2511 Background: PF-06647263 is an anti-Ephrin-A4 (EFNA4) antibody drug conjugate (ADC) composed ... more 2511 Background: PF-06647263 is an anti-Ephrin-A4 (EFNA4) antibody drug conjugate (ADC) composed of a humanized mAb, a hydrazone cleavable linker, and calicheamicin, a potent DNA damaging agent. Higher levels of EFNA4 expression have been shown in tumor versus normal tissue, including in two thirds of triple negative breast cancers (TNBC). In vivo preclinical studies demonstrate PF-06647263 induced tumor regression in TNBC models. Methods: In Part 1 of a dose escalation, cohorts of 2-12 patient (pts) with solid tumors that were unselected for EFNA4 expression received escalating doses of PF-06647263 once every 3 weeks (Q3W, Cohort A) or weekly (QW, Cohort B). Escalations were based on mTPI design. An expansion cohort enrolled TNBC patients (n=12) unselected for EFNA4 expression. Efficacy, safety, EFNA4 RNA expression, pharmacokinetic (PK) and anti-drug antibody development were assessed. Results: Part 1 (dose escalation):A total of 48 pts (25 in A and 23 in B) wereenrolled. The most common treatment related adverse events (AE) were fatigue (65%), and nausea (60%), thrombocytopenia (40%), and decreased appetite (38%). DLTs were observed in 6 and 2 pts in the Q3W and QW regimens, respectively. One confirmed VOD and one suspected VOD were observed in two patients in the Q3W schedule. The maximum tolerated dose (and RP2D) was determined to be 0.015 mg/kg QW. Confirmed partial responses (PR) were observed in 5 pts (3 Ovarian Ca and 2 TNBC). Part 2 (TNBC dose expansion at RP2D)data are available on 10 of 12 pts treated (2 ongoing). The most common adverse events (AE) were nausea (40%), asthenia (30%), vomiting (30%) and mucosal inflammation (30%). No objective RECIST response was observed; there was no dependency with duration of treatment relative to EFNA4 expression. Conclusions: In Part 1 of this study, PF-06647263 was generally well-tolerated in the QW schedule and some anti-tumor activity was observed in heavily pretreated pts with EFNA4 unselected advanced malignancies. However, in the expansion cohort (Part 2) at RP2D in TNBC no objective responses were observed regardless of EFNA4 expression. Final safety, efficacy, expression and PK data will be reported at the meeting. Clinical trial information: NCT02078752.
e13042 Background: Cabozantinib is an oral, potent inhibitor of MET and VEGFR2 that is currently ... more e13042 Background: Cabozantinib is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing clinical efficacy evaluation in several oncology indications. In parallel, clinical pharmacology studies are being performed, including assessment of potential drug-drug interactions (DDIs). Renal cell carcinoma (RCC) and differentiated thyroid cancer (DTC) were chosen as indications in this study based on involvement of the MET and VEGFR signaling pathways in these indications. The primary objective of this study is to determine the effect of cabozantinib on single dose PK of the CYP2C8 substrate rosiglitazone. The exploratory objective of this study is to evaluate the preliminary antitumor activity of cabozantinib in pts with RCC and DTC. METHODS Approximately 35 cancer pts initially limited to DTC or RCC may be enrolled to this study. On study Day 1, pts receive a 4 mg tablet of rosiglitazone; PK sampling is completed on Day 2. On Days 2 (post PK sampling) through 21, cabozantinib is administered daily at a starting dose of 175 mg. On study Day 22 pts receive rosiglitazone 4 mg tablet and complete PK assessments. On study Day 57 and every 8 weeks thereafter subjects undergo tumor assessments by mRECIST. RESULTS To date, 10 pts (9 RCC; 1 DTC) have been enrolled (20 pts anticipated by May 2011). All pts had measurable disease. Median number of prior regimens was 3 (7/9 RCC pts with ≥ 2 lines of prior therapy and 6/9 with at least 1 VEGF pathway inhibitor and 1 mTOR inhibitor). No marked differences in concentration profiles, Tmax, Cmax, or AUC0-24h values were observed in 4 pts who completed the PK portion. Overall, 4/9 RCC pts had a confirmed partial response; 7/10 pts experienced tumor regression (16-49%). Related AEs ≥Grade 3 severity: fatigue (1 pt), amylase and lipase increased and hypophosphatemia (1 pt), and hyponatremia and hypophosphatemia (1 pt). CONCLUSIONS Preliminary data suggests no drug-drug interactions between cabozantinib and rosiglitazone (CYP2C8 substrate). Cabozantinib demonstrates anti-tumor activity in heavily pretreated pts with RCC.
364 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is curren... more 364 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing clinical efficacy evaluation in several oncology indications. Renal cell carcinoma (RCC) was chosen as an indication in this drug-drug interaction (DDI) study based on involvement of the MET and VEGFR signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). The exploratory objective of this study is to evaluate the preliminary antitumor activity of cabo in pts with RCC. Methods: Eligible pts were required to have RCC with clear cell components with metastases, Karnofsky performance status of ≥70 and measurable disease by RECIST. Pts needed to have experienced PD following standard therapies. Method for DDI study: Day 1, 4 mg rosi; Days 2 - 22, cabo given daily at a dose of 175 mg; Day 22, 4 mg rosi to complete PK assessment for DDI. Cabo continued until PD. On Day 57 and every 8 weeks thereafter subjects underwent tumor assessments by mRECIST. Results: Enrollment is complete at 25 RCC pts with a median of 2 prior regimens; 17/25 (68%) RCC pts had received ≥ 2 lines of prior therapy and 13/25 (52%) with at least 1 VEGF pathway inhibitor and 1 mTOR inhibitor. All pts were intermediate (24/25) or poor (1/25) risk category per Heng et al prognostic strata (JCO 2009). Related AEs ≥ Grade 3 severity: hypophosphatemia 8 (32%), PE 3 (12%; all were incidental / resolved) and diarrhea 3 (12%). Preliminary PK data suggest that clinically relevant doses of cabo do not markedly alter the Cmax or AUC0-24h of rosi consistent with lack of inhibition of CYP2C8. RCC pts with confirmed PR by mRECIST: 6/25 (24%). Additionally, 1 pt had an unconfirmed PR. Disease control rate (PR + SD): 68% at 16 weeks; 18/21 (86%) pts with ≥1 post-baseline scan experienced tumor regression (range: 4 – 63% reduction in measurements). 14/25 (56%) remain on cabo with a median follow-up of 4 months. Median PFS and OS have not been reached. Conclusions: Cabo demonstrates encouraging anti-tumor activity in heavily pretreated pts with RCC with a toxicity profile similar to that of other TKIs. Preliminary data suggest no DDI between cabo and rosi (CYP2C8 substrate).
TPS2679 Background: In 2022 approximately 1.7 million Americans will die from solid cancers. Rece... more TPS2679 Background: In 2022 approximately 1.7 million Americans will die from solid cancers. Recently there have been significant advances in the genetic engineering of T lymphocytes to recognize neoantigens on tumors in vivo, resulting in remarkable cases of tumor regression and remission. Cancer cells frequently harbor KRAS, TP53, and EGFR somatic hotspot mutations that can be processed and presented by tumor HLA as neoantigens to T cells through their T-cell receptor (TCR). These neoantigens are not present in the normal tissues; thus, they are attractive targets for adoptive T cell therapy. Given the number and complexity of different neoantigen/HLA combinations on solid tumors, a TCR library approach is warranted. Therefore, we have developed a library of TCR-T cell therapies including those targeting shared KRAS, TP53 and EGFR mutations. Methods: Patients for whom a TCR matching the subject’s somatic mutation(s) and HLA type is available in our TCR library, and have progressiv...
La presente invention concerne une methode de quantification de la reponse a un traitement anti-c... more La presente invention concerne une methode de quantification de la reponse a un traitement anti-cancereux chez des patients presentant des metastases osseuses au moyen d'une evaluation par scintigraphie osseuse assistee par ordinateur. La methode consiste a : (a) obtenir une image de scintigraphie osseuse; (b) normaliser l'image obtenue par scintigraphie osseuse pour identifier des lesions normalisees de la scintigraphie osseuse; et (c) evaluer quantitativement les lesions normalisees de la scintigraphie osseuse a l'aide d'une zone de lesions de la scintigraphie osseuse, de l'intensite de la scintigraphie osseuse ou du nombre de lesions de la scintigraphie osseuse.
Background Relapsed/refractory follicular lymphoma (FL) is a challenging disease; novel therapeut... more Background Relapsed/refractory follicular lymphoma (FL) is a challenging disease; novel therapeutics with different mechanisms of action are needed. Spleen tyrosine kinase (SYK) and Janus kinase (JAK) signaling pathways are activated in FL and appear to play important roles in tumor survival. Cerdulatinib (ALXN2075) is an orally active, small molecule, reversible ATP-competitive dual inhibitor of SYK/JAK (JAK1, JAK2, TYK2) family members. The clinical activity and safety of cerdulatinib monotherapy were investigated in a multicenter, single-arm Phase 2a dose-expansion study (NCT01994382) of patients (pts) with T- or B-cell malignancies (N=220), including relapsed/refractory FL. Methods Eligible pts were aged ≥18 years with histologically confirmed FL (grade 1-3A) and relapsed/refractory disease after ≥1 systemic therapy (≥2 cycles including an anti-CD20 agent [e.g. rituximab] + chemotherapy, unless contraindicated). Pts with relapsed/refractory FL were initially enrolled in the mono...
Repeated blood transfusion to prevent complications places patients with sickle cell disease at r... more Repeated blood transfusion to prevent complications places patients with sickle cell disease at risk for morbidity from chronic iron overload. Parenteral chelation with deferoxamine (DFO) is effective at reducing iron overload but patient compliance is generally poor. Deferasirox (DSX) is an investigational iron chelator given orally once-daily. Demonstration of the safety and tolerability of DSX over a 1-year period was the primary objective and efficacy was a secondary objective of the study. Adult and pediatric patients (n=195; n=98 aged <16) were randomized 2:1 to receive treatment with DSX (n=132) or DFO (n=63). Dosing of DSX from 5 to 30 mg/kg/day and DFO from 20 to 60 mg/kg/day was based upon baseline liver iron concentration (LIC) as determined by liver susceptometry using a superconducting quantum interference device (SQUID). Initial DSX doses <20 mg/kg were increased midway through the trial based upon emerging data from other DSX trials. Safety assessments included ...
Nilotinib, a selective and potent inhibitor of Bcr-Abl tyrosine kinase, has demonstrated activity... more Nilotinib, a selective and potent inhibitor of Bcr-Abl tyrosine kinase, has demonstrated activity at 400 mg twice daily dosing against imatinib-resistant forms of Bcr-Abl in patients with CML or Ph+ALL in an open label phase I/II study. In this patient population, elevated liver transaminases levels over baseline, which may be related to a combination of past medical history and the hepatotoxic effects of previous medications, are frequently observed but are generally mild and self-limiting. Nilotinib is metabolized in the liver by CYP3A4, and the metabolites are excreted exclusively via the bile into feces. This study was designed to assess pharmacokinetics of nilotinib across a broad spectrum of hepatic impairment in comparison to a control group with normal hepatic function in order to provide guidance for the safe use of the drug in patients with hepatic impairment. Hepatic impairment was categorized using the three Child-Pugh categories (mild, moderate, and severe). The demogra...
Introduction: HIC is a surrogate for total body iron in pts with transfusional iron overload. MRI... more Introduction: HIC is a surrogate for total body iron in pts with transfusional iron overload. MRI techniques based on signal intensity ratios (SIR) or relaxation rates (R2 and R2*) are increasingly accepted as surrogates to biopsy in determining HIC. MRI techniques have been validated using data acquired on different MRI platforms, but image processing has been restricted to labs where the techniques were developed. We tested the ability of an imaging core lab to process data from 4 different MRI techniques:Gradient echo (GE) SIR (Gandon et al);Spin echo (SE) SIR (Jensen et al);R2 (Wood et al);R2* (Wood et al). R2 St. Pierre processing is proprietary and was not implemented by the core lab. The goal was to collect pilot data to test the feasibility of independent core lab assessment as well as assess inter-technique agreement and interobserver variability. Methods: Seven CICL670A0109 MRI/liver biopsy substudy pts (all at CHLA; one withdrew after baseline [BL] exam) participated in a...
1. Am J Hosp Pharm. 1994 Feb 15;51(4):514-7. Stability of dexamethasone sodium phosphate, diphenh... more 1. Am J Hosp Pharm. 1994 Feb 15;51(4):514-7. Stability of dexamethasone sodium phosphate, diphenhydramine hydrochloride, lorazepam, and metoclopramide hydrochloride in portable infusion-pump reservoirs. Stiles ML, Allen LV Jr, Prince SJ, Holland JS. ...
PF‐06647263, a novel antibody–drug conjugate consisting of an anti‐EFNA4 antibody linked to a cal... more PF‐06647263, a novel antibody–drug conjugate consisting of an anti‐EFNA4 antibody linked to a calicheamicin payload, has shown potent antitumor activity in human xenograft tumor models, including triple‐negative breast cancer (TNBC). In the dose‐escalation part 1 of this multicenter, open‐label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF‐06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W). Primary objective in part 1 was to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). In part 2 (dose‐expansion cohort), 12 patients with pretreated, metastatic TNBC received PF‐06647263 at the RP2D to further evaluate tumor response and overall safety. PF‐06647263 QW administration (n, 23) was better tolerated than the Q3W regimen (n, 25) with only 1 DLT reported (thr...
2511 Background: PF-06647263 is an anti-Ephrin-A4 (EFNA4) antibody drug conjugate (ADC) composed ... more 2511 Background: PF-06647263 is an anti-Ephrin-A4 (EFNA4) antibody drug conjugate (ADC) composed of a humanized mAb, a hydrazone cleavable linker, and calicheamicin, a potent DNA damaging agent. Higher levels of EFNA4 expression have been shown in tumor versus normal tissue, including in two thirds of triple negative breast cancers (TNBC). In vivo preclinical studies demonstrate PF-06647263 induced tumor regression in TNBC models. Methods: In Part 1 of a dose escalation, cohorts of 2-12 patient (pts) with solid tumors that were unselected for EFNA4 expression received escalating doses of PF-06647263 once every 3 weeks (Q3W, Cohort A) or weekly (QW, Cohort B). Escalations were based on mTPI design. An expansion cohort enrolled TNBC patients (n=12) unselected for EFNA4 expression. Efficacy, safety, EFNA4 RNA expression, pharmacokinetic (PK) and anti-drug antibody development were assessed. Results: Part 1 (dose escalation):A total of 48 pts (25 in A and 23 in B) wereenrolled. The most...
141 Background: Cabo inhibits tyrosine kinases including MET and VEGFRs. In a phase 2 study in mC... more 141 Background: Cabo inhibits tyrosine kinases including MET and VEGFRs. In a phase 2 study in mCRPC pts, Cabo was associated with improvements in pain, bone scans, measurable disease, and circulating tumor cells. COMET-2 compared the effects of Cabo versus MP on pain palliation in men with progressive mCRPC. Methods: In this double-blind, controlled phase 3 study (NCT01522443), pts with moderate to severe pain and disease progression following D, and A and/or E were randomized 1:1 to receive Cabo (60 mg qd) or MP (12 mg/m2 q3wk and 5 mg bid, resp). All pts were required to have a 7-day average of 4+ pain per Brief Pain Inventory (BPI) item 3 while on an optimized narcotics regimen at baseline. Randomization was stratified by prior cabazitaxel and ECOG performance status. The primary endpoint was pain response (≥30% reduction in BPI item 3) at week 6, confirmed at week 12, without increase in narcotics. The original sample size (N = 246) was selected to achieve at least 90% power to...
364 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is curren... more 364 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing clinical efficacy evaluation in several oncology indications. Renal cell carcinoma (RCC) was chosen as an indication in this drug-drug interaction (DDI) study based on involvement of the MET and VEGFR signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). The exploratory objective of this study is to evaluate the preliminary antitumor activity of cabo in pts with RCC. Methods: Eligible pts were required to have RCC with clear cell components with metastases, Karnofsky performance status of ≥70 and measurable disease by RECIST. Pts needed to have experienced PD following standard therapies. Method for DDI study: Day 1, 4 mg rosi; Days 2 - 22, cabo given daily at a dose of 175 mg; Day 22, 4 mg rosi to complete PK assessment for DDI. Cabo continued until PD. On ...
2511 Background: PF-06647263 is an anti-Ephrin-A4 (EFNA4) antibody drug conjugate (ADC) composed ... more 2511 Background: PF-06647263 is an anti-Ephrin-A4 (EFNA4) antibody drug conjugate (ADC) composed of a humanized mAb, a hydrazone cleavable linker, and calicheamicin, a potent DNA damaging agent. Higher levels of EFNA4 expression have been shown in tumor versus normal tissue, including in two thirds of triple negative breast cancers (TNBC). In vivo preclinical studies demonstrate PF-06647263 induced tumor regression in TNBC models. Methods: In Part 1 of a dose escalation, cohorts of 2-12 patient (pts) with solid tumors that were unselected for EFNA4 expression received escalating doses of PF-06647263 once every 3 weeks (Q3W, Cohort A) or weekly (QW, Cohort B). Escalations were based on mTPI design. An expansion cohort enrolled TNBC patients (n=12) unselected for EFNA4 expression. Efficacy, safety, EFNA4 RNA expression, pharmacokinetic (PK) and anti-drug antibody development were assessed. Results: Part 1 (dose escalation):A total of 48 pts (25 in A and 23 in B) wereenrolled. The most common treatment related adverse events (AE) were fatigue (65%), and nausea (60%), thrombocytopenia (40%), and decreased appetite (38%). DLTs were observed in 6 and 2 pts in the Q3W and QW regimens, respectively. One confirmed VOD and one suspected VOD were observed in two patients in the Q3W schedule. The maximum tolerated dose (and RP2D) was determined to be 0.015 mg/kg QW. Confirmed partial responses (PR) were observed in 5 pts (3 Ovarian Ca and 2 TNBC). Part 2 (TNBC dose expansion at RP2D)data are available on 10 of 12 pts treated (2 ongoing). The most common adverse events (AE) were nausea (40%), asthenia (30%), vomiting (30%) and mucosal inflammation (30%). No objective RECIST response was observed; there was no dependency with duration of treatment relative to EFNA4 expression. Conclusions: In Part 1 of this study, PF-06647263 was generally well-tolerated in the QW schedule and some anti-tumor activity was observed in heavily pretreated pts with EFNA4 unselected advanced malignancies. However, in the expansion cohort (Part 2) at RP2D in TNBC no objective responses were observed regardless of EFNA4 expression. Final safety, efficacy, expression and PK data will be reported at the meeting. Clinical trial information: NCT02078752.
e13042 Background: Cabozantinib is an oral, potent inhibitor of MET and VEGFR2 that is currently ... more e13042 Background: Cabozantinib is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing clinical efficacy evaluation in several oncology indications. In parallel, clinical pharmacology studies are being performed, including assessment of potential drug-drug interactions (DDIs). Renal cell carcinoma (RCC) and differentiated thyroid cancer (DTC) were chosen as indications in this study based on involvement of the MET and VEGFR signaling pathways in these indications. The primary objective of this study is to determine the effect of cabozantinib on single dose PK of the CYP2C8 substrate rosiglitazone. The exploratory objective of this study is to evaluate the preliminary antitumor activity of cabozantinib in pts with RCC and DTC. METHODS Approximately 35 cancer pts initially limited to DTC or RCC may be enrolled to this study. On study Day 1, pts receive a 4 mg tablet of rosiglitazone; PK sampling is completed on Day 2. On Days 2 (post PK sampling) through 21, cabozantinib is administered daily at a starting dose of 175 mg. On study Day 22 pts receive rosiglitazone 4 mg tablet and complete PK assessments. On study Day 57 and every 8 weeks thereafter subjects undergo tumor assessments by mRECIST. RESULTS To date, 10 pts (9 RCC; 1 DTC) have been enrolled (20 pts anticipated by May 2011). All pts had measurable disease. Median number of prior regimens was 3 (7/9 RCC pts with ≥ 2 lines of prior therapy and 6/9 with at least 1 VEGF pathway inhibitor and 1 mTOR inhibitor). No marked differences in concentration profiles, Tmax, Cmax, or AUC0-24h values were observed in 4 pts who completed the PK portion. Overall, 4/9 RCC pts had a confirmed partial response; 7/10 pts experienced tumor regression (16-49%). Related AEs ≥Grade 3 severity: fatigue (1 pt), amylase and lipase increased and hypophosphatemia (1 pt), and hyponatremia and hypophosphatemia (1 pt). CONCLUSIONS Preliminary data suggests no drug-drug interactions between cabozantinib and rosiglitazone (CYP2C8 substrate). Cabozantinib demonstrates anti-tumor activity in heavily pretreated pts with RCC.
364 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is curren... more 364 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing clinical efficacy evaluation in several oncology indications. Renal cell carcinoma (RCC) was chosen as an indication in this drug-drug interaction (DDI) study based on involvement of the MET and VEGFR signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). The exploratory objective of this study is to evaluate the preliminary antitumor activity of cabo in pts with RCC. Methods: Eligible pts were required to have RCC with clear cell components with metastases, Karnofsky performance status of ≥70 and measurable disease by RECIST. Pts needed to have experienced PD following standard therapies. Method for DDI study: Day 1, 4 mg rosi; Days 2 - 22, cabo given daily at a dose of 175 mg; Day 22, 4 mg rosi to complete PK assessment for DDI. Cabo continued until PD. On Day 57 and every 8 weeks thereafter subjects underwent tumor assessments by mRECIST. Results: Enrollment is complete at 25 RCC pts with a median of 2 prior regimens; 17/25 (68%) RCC pts had received ≥ 2 lines of prior therapy and 13/25 (52%) with at least 1 VEGF pathway inhibitor and 1 mTOR inhibitor. All pts were intermediate (24/25) or poor (1/25) risk category per Heng et al prognostic strata (JCO 2009). Related AEs ≥ Grade 3 severity: hypophosphatemia 8 (32%), PE 3 (12%; all were incidental / resolved) and diarrhea 3 (12%). Preliminary PK data suggest that clinically relevant doses of cabo do not markedly alter the Cmax or AUC0-24h of rosi consistent with lack of inhibition of CYP2C8. RCC pts with confirmed PR by mRECIST: 6/25 (24%). Additionally, 1 pt had an unconfirmed PR. Disease control rate (PR + SD): 68% at 16 weeks; 18/21 (86%) pts with ≥1 post-baseline scan experienced tumor regression (range: 4 – 63% reduction in measurements). 14/25 (56%) remain on cabo with a median follow-up of 4 months. Median PFS and OS have not been reached. Conclusions: Cabo demonstrates encouraging anti-tumor activity in heavily pretreated pts with RCC with a toxicity profile similar to that of other TKIs. Preliminary data suggest no DDI between cabo and rosi (CYP2C8 substrate).
TPS2679 Background: In 2022 approximately 1.7 million Americans will die from solid cancers. Rece... more TPS2679 Background: In 2022 approximately 1.7 million Americans will die from solid cancers. Recently there have been significant advances in the genetic engineering of T lymphocytes to recognize neoantigens on tumors in vivo, resulting in remarkable cases of tumor regression and remission. Cancer cells frequently harbor KRAS, TP53, and EGFR somatic hotspot mutations that can be processed and presented by tumor HLA as neoantigens to T cells through their T-cell receptor (TCR). These neoantigens are not present in the normal tissues; thus, they are attractive targets for adoptive T cell therapy. Given the number and complexity of different neoantigen/HLA combinations on solid tumors, a TCR library approach is warranted. Therefore, we have developed a library of TCR-T cell therapies including those targeting shared KRAS, TP53 and EGFR mutations. Methods: Patients for whom a TCR matching the subject’s somatic mutation(s) and HLA type is available in our TCR library, and have progressiv...
La presente invention concerne une methode de quantification de la reponse a un traitement anti-c... more La presente invention concerne une methode de quantification de la reponse a un traitement anti-cancereux chez des patients presentant des metastases osseuses au moyen d'une evaluation par scintigraphie osseuse assistee par ordinateur. La methode consiste a : (a) obtenir une image de scintigraphie osseuse; (b) normaliser l'image obtenue par scintigraphie osseuse pour identifier des lesions normalisees de la scintigraphie osseuse; et (c) evaluer quantitativement les lesions normalisees de la scintigraphie osseuse a l'aide d'une zone de lesions de la scintigraphie osseuse, de l'intensite de la scintigraphie osseuse ou du nombre de lesions de la scintigraphie osseuse.
Background Relapsed/refractory follicular lymphoma (FL) is a challenging disease; novel therapeut... more Background Relapsed/refractory follicular lymphoma (FL) is a challenging disease; novel therapeutics with different mechanisms of action are needed. Spleen tyrosine kinase (SYK) and Janus kinase (JAK) signaling pathways are activated in FL and appear to play important roles in tumor survival. Cerdulatinib (ALXN2075) is an orally active, small molecule, reversible ATP-competitive dual inhibitor of SYK/JAK (JAK1, JAK2, TYK2) family members. The clinical activity and safety of cerdulatinib monotherapy were investigated in a multicenter, single-arm Phase 2a dose-expansion study (NCT01994382) of patients (pts) with T- or B-cell malignancies (N=220), including relapsed/refractory FL. Methods Eligible pts were aged ≥18 years with histologically confirmed FL (grade 1-3A) and relapsed/refractory disease after ≥1 systemic therapy (≥2 cycles including an anti-CD20 agent [e.g. rituximab] + chemotherapy, unless contraindicated). Pts with relapsed/refractory FL were initially enrolled in the mono...
Repeated blood transfusion to prevent complications places patients with sickle cell disease at r... more Repeated blood transfusion to prevent complications places patients with sickle cell disease at risk for morbidity from chronic iron overload. Parenteral chelation with deferoxamine (DFO) is effective at reducing iron overload but patient compliance is generally poor. Deferasirox (DSX) is an investigational iron chelator given orally once-daily. Demonstration of the safety and tolerability of DSX over a 1-year period was the primary objective and efficacy was a secondary objective of the study. Adult and pediatric patients (n=195; n=98 aged <16) were randomized 2:1 to receive treatment with DSX (n=132) or DFO (n=63). Dosing of DSX from 5 to 30 mg/kg/day and DFO from 20 to 60 mg/kg/day was based upon baseline liver iron concentration (LIC) as determined by liver susceptometry using a superconducting quantum interference device (SQUID). Initial DSX doses <20 mg/kg were increased midway through the trial based upon emerging data from other DSX trials. Safety assessments included ...
Nilotinib, a selective and potent inhibitor of Bcr-Abl tyrosine kinase, has demonstrated activity... more Nilotinib, a selective and potent inhibitor of Bcr-Abl tyrosine kinase, has demonstrated activity at 400 mg twice daily dosing against imatinib-resistant forms of Bcr-Abl in patients with CML or Ph+ALL in an open label phase I/II study. In this patient population, elevated liver transaminases levels over baseline, which may be related to a combination of past medical history and the hepatotoxic effects of previous medications, are frequently observed but are generally mild and self-limiting. Nilotinib is metabolized in the liver by CYP3A4, and the metabolites are excreted exclusively via the bile into feces. This study was designed to assess pharmacokinetics of nilotinib across a broad spectrum of hepatic impairment in comparison to a control group with normal hepatic function in order to provide guidance for the safe use of the drug in patients with hepatic impairment. Hepatic impairment was categorized using the three Child-Pugh categories (mild, moderate, and severe). The demogra...
Introduction: HIC is a surrogate for total body iron in pts with transfusional iron overload. MRI... more Introduction: HIC is a surrogate for total body iron in pts with transfusional iron overload. MRI techniques based on signal intensity ratios (SIR) or relaxation rates (R2 and R2*) are increasingly accepted as surrogates to biopsy in determining HIC. MRI techniques have been validated using data acquired on different MRI platforms, but image processing has been restricted to labs where the techniques were developed. We tested the ability of an imaging core lab to process data from 4 different MRI techniques:Gradient echo (GE) SIR (Gandon et al);Spin echo (SE) SIR (Jensen et al);R2 (Wood et al);R2* (Wood et al). R2 St. Pierre processing is proprietary and was not implemented by the core lab. The goal was to collect pilot data to test the feasibility of independent core lab assessment as well as assess inter-technique agreement and interobserver variability. Methods: Seven CICL670A0109 MRI/liver biopsy substudy pts (all at CHLA; one withdrew after baseline [BL] exam) participated in a...
1. Am J Hosp Pharm. 1994 Feb 15;51(4):514-7. Stability of dexamethasone sodium phosphate, diphenh... more 1. Am J Hosp Pharm. 1994 Feb 15;51(4):514-7. Stability of dexamethasone sodium phosphate, diphenhydramine hydrochloride, lorazepam, and metoclopramide hydrochloride in portable infusion-pump reservoirs. Stiles ML, Allen LV Jr, Prince SJ, Holland JS. ...
PF‐06647263, a novel antibody–drug conjugate consisting of an anti‐EFNA4 antibody linked to a cal... more PF‐06647263, a novel antibody–drug conjugate consisting of an anti‐EFNA4 antibody linked to a calicheamicin payload, has shown potent antitumor activity in human xenograft tumor models, including triple‐negative breast cancer (TNBC). In the dose‐escalation part 1 of this multicenter, open‐label, phase I study (NCT02078752), successive cohorts of patients (n, 48) with advanced solid tumors and no available standard therapy received PF‐06647263 every 3 weeks (Q3W) or every week (QW), following a modified toxicity probability interval (mTPI) method (initial dosing: 0.015 mg/kg Q3W). Primary objective in part 1 was to estimate the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D). In part 2 (dose‐expansion cohort), 12 patients with pretreated, metastatic TNBC received PF‐06647263 at the RP2D to further evaluate tumor response and overall safety. PF‐06647263 QW administration (n, 23) was better tolerated than the Q3W regimen (n, 25) with only 1 DLT reported (thr...
2511 Background: PF-06647263 is an anti-Ephrin-A4 (EFNA4) antibody drug conjugate (ADC) composed ... more 2511 Background: PF-06647263 is an anti-Ephrin-A4 (EFNA4) antibody drug conjugate (ADC) composed of a humanized mAb, a hydrazone cleavable linker, and calicheamicin, a potent DNA damaging agent. Higher levels of EFNA4 expression have been shown in tumor versus normal tissue, including in two thirds of triple negative breast cancers (TNBC). In vivo preclinical studies demonstrate PF-06647263 induced tumor regression in TNBC models. Methods: In Part 1 of a dose escalation, cohorts of 2-12 patient (pts) with solid tumors that were unselected for EFNA4 expression received escalating doses of PF-06647263 once every 3 weeks (Q3W, Cohort A) or weekly (QW, Cohort B). Escalations were based on mTPI design. An expansion cohort enrolled TNBC patients (n=12) unselected for EFNA4 expression. Efficacy, safety, EFNA4 RNA expression, pharmacokinetic (PK) and anti-drug antibody development were assessed. Results: Part 1 (dose escalation):A total of 48 pts (25 in A and 23 in B) wereenrolled. The most...
141 Background: Cabo inhibits tyrosine kinases including MET and VEGFRs. In a phase 2 study in mC... more 141 Background: Cabo inhibits tyrosine kinases including MET and VEGFRs. In a phase 2 study in mCRPC pts, Cabo was associated with improvements in pain, bone scans, measurable disease, and circulating tumor cells. COMET-2 compared the effects of Cabo versus MP on pain palliation in men with progressive mCRPC. Methods: In this double-blind, controlled phase 3 study (NCT01522443), pts with moderate to severe pain and disease progression following D, and A and/or E were randomized 1:1 to receive Cabo (60 mg qd) or MP (12 mg/m2 q3wk and 5 mg bid, resp). All pts were required to have a 7-day average of 4+ pain per Brief Pain Inventory (BPI) item 3 while on an optimized narcotics regimen at baseline. Randomization was stratified by prior cabazitaxel and ECOG performance status. The primary endpoint was pain response (≥30% reduction in BPI item 3) at week 6, confirmed at week 12, without increase in narcotics. The original sample size (N = 246) was selected to achieve at least 90% power to...
364 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is curren... more 364 Background: Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2 that is currently undergoing clinical efficacy evaluation in several oncology indications. Renal cell carcinoma (RCC) was chosen as an indication in this drug-drug interaction (DDI) study based on involvement of the MET and VEGFR signaling pathways in this disease. The primary objective of this study is to determine the effect of cabo on single dose PK of the CYP2C8 substrate rosiglitazone (rosi). The exploratory objective of this study is to evaluate the preliminary antitumor activity of cabo in pts with RCC. Methods: Eligible pts were required to have RCC with clear cell components with metastases, Karnofsky performance status of ≥70 and measurable disease by RECIST. Pts needed to have experienced PD following standard therapies. Method for DDI study: Day 1, 4 mg rosi; Days 2 - 22, cabo given daily at a dose of 175 mg; Day 22, 4 mg rosi to complete PK assessment for DDI. Cabo continued until PD. On ...
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