Donald A. Richards

Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial

BACKGROUND Chemoimmunotherapy has led to improved numbers of patients achieving disease response, and longer overall survival in young patients with chronic lymphocytic leukaemia; however, its application in elderly patients has been restricted by substantial myelosuppression and infection. We aimed to assess safety and activity of ibrutinib, an orally administered covalent inhibitor of Bruton tyrosine kinase (BTK), in treatment-naive patients aged 65 years and older with chronic lymphocytic leukaemia. METHODS In our open-label phase 1b/2 trial, we enrolled previously untreated patients at clinical sites in the USA. Eligible patients were aged at least 65 years, and had symptomatic chronic lymphocytic leukaemia or small lymphocytic lymphoma requiring therapy. Patients received 28 day cycles of once-daily ibrutinib 420 mg or ibrutinib 840 mg. The 840 mg dose was discontinued after enrolment had begun because comparable activity of the doses has been shown. The primary endpoint was the safety of the dose-fixed regimen in terms of frequency and severity of adverse events for all patients who received treatment. This study is registered with ClinicalTrials.gov, number NCT01105247. FINDINGS Between May 20, 2010, and Dec 18, 2012, we enrolled 29 patients with chronic lymphocytic leukaemia and two patients with small lymphocytic lymphoma. Median age was 71 years (range 65-84), and 23 (74%) patients were at least 70 years old. Toxicity was mainly of mild-to-moderate severity (grade 1-2). 21 (68%) patients had diarrhoea (grade 1 in 14 [45%] patients, grade 2 in three [10%] patients, and grade 3 in four [13%] patients). 15 (48%) patients developed nausea (grade 1 in 12 [39%] patients and grade 2 in three [10%] patients). Ten (32%) patients developed fatigue (grade 1 in five [16%] patients, grade 2 in four [13%] patients, and grade 3 in one [3%] patient). Three (10%) patients developed grade 3 infections, although no grade 4 or 5 infections occurred. One patient developed grade 3 neutropenia, and one developed grade 4 thrombocytopenia. After a median follow-up of 22.1 months (IQR 18.4-23.2), 22 (71%) of 31 patients achieved an objective response (95% CI 52.0-85.8); four patients (13%) had a complete response, one patient (3%) had a nodular partial response, and 17 (55%) patients had a partial response. INTERPRETATION The safety and activity of ibrutinib in elderly, previously untreated patients with symptomatic chronic lymphocytic leukaemia, or small lymphocytic lymphoma is encouraging, and merits further investigation in phase 3 trials. FUNDING Pharmacyclics, Leukemia and Lymphoma Society, D Warren Brown Foundation, Mr and Mrs Michael Thomas, Harry Mangurian Foundation, P50 CA140158 to Prof J C Byrd MD.

Phase I Evaluation of ISIS 3521, an Antisense Oligodeoxynucleotide to Protein Kinase C-Alpha, in Patients With Advanced Cancer

PURPOSE To determine the maximum-tolerated dose (MTD) and pharmacologic behavior of ISIS 3521 (ISI 641A), an antisense phosphorothioate oligonucleotide to protein kinase C-alpha. PATIENTS AND METHODS Thirty-six patients with advanced cancer received 99 cycles of ISIS 3521 (0.15 to 6.0 mg/kg/d) as a 2-hour intravenous infusion administered three times per week for 3 consecutive weeks and repeated every 4 weeks. Plasma and urine sampling was performed during the first week of treatment and subjected to capillary gel electrophoresis to determine full-length antisense oligonucleotide in addition to chain-shortened metabolites. RESULTS Drug-related toxicities included mild to moderate nausea, vomiting, fever, chills, and fatigue. Hematologic toxicity was limited to thrombocytopenia (grade 1, four patients; grade 2, one patient; grade 3, one patient). There was no relationship between dose, maximum concentration of the drug (C(max)), or area under the plasma concentration versus time curve (AUC) and coagulation times or complement levels. Dose escalation was discontinued because of the attainment of peak plasma concentrations, which approached that associated with complement activation in primates. Two patients with non-Hodgkins lymphoma who completed 17 and nine cycles of therapy achieved complete responses. The pharmacokinetic profile of ISIS 3521 revealed a short elimination half-life (18 to 92 minutes), as well as a dose-dependent decrease in clearance and dose-dependent increases in C(max), AUC, and elimination half-life. CONCLUSION No dose-limiting toxicity of ISIS 3521 was identified, and clinical activity was observed. A short elimination half-life was identified, which suggests that alternate schedules with prolonged administration may be necessary for further clinical development.

A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer

BACKGROUND We evaluated the efficacy and safety of ganitumab (a mAb antagonist of insulin-like growth factor 1 receptor) or conatumumab (a mAb agonist of human death receptor 5) combined with gemcitabine in a randomized phase 2 trial in patients with metastatic pancreatic cancer. PATIENTS AND METHODS Patients with a previously untreated metastatic pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 were randomized 1 : 1 : 1 to i.v. gemcitabine 1000 mg/m(2) (days 1, 8, and 15 of each 28-day cycle) combined with open-label ganitumab (12 mg/kg every 2 weeks [Q2W]), double-blind conatumumab (10 mg/kg Q2W), or double-blind placebo Q2W. The primary end point was 6-month survival rate. Results In total, 125 patients were randomized. The 6-month survival rates were 57% (95% CI 41-70) in the ganitumab arm, 59% (42-73) in the conatumumab arm, and 50% (33-64) in the placebo arm. The grade ≥3 adverse events in the ganitumab, conatumumab, and placebo arms, respectively, included neutropenia (18/22/13%), thrombocytopenia (15/17/8%), fatigue (13/12/5%), alanine aminotransferase increase (15/5/8%), and hyperglycemia (18/2/3%). CONCLUSIONS Ganitumab combined with gemcitabine had tolerable toxicity and showed trends toward an improved 6-month survival rate and overall survival. Additional investigation into this combination is warranted. Conatumumab combined with gemcitabine showed some evidence of activity as assessed by the 6-month survival rate.BACKGROUND We evaluated the efficacy and safety of ganitumab (a mAb antagonist of insulin-like growth factor 1 receptor) or conatumumab (a mAb agonist of human death receptor 5) combined with gemcitabine in a randomized phase 2 trial in patients with metastatic pancreatic cancer. PATIENTS AND METHODS Patients with a previously untreated metastatic pancreatic adenocarcinoma and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 were randomized 1 : 1 : 1 to i.v. gemcitabine 1000 mg/m2 (days 1, 8, and 15 of each 28-day cycle) combined with open-label ganitumab (12 mg/kg every 2 weeks [Q2W]), double-blind conatumumab (10 mg/kg Q2W), or double-blind placebo Q2W. The primary end point was 6-month survival rate. RESULTS In total, 125 patients were randomized. The 6-month survival rates were 57% (95% CI 41-70) in the ganitumab arm, 59% (42-73) in the conatumumab arm, and 50% (33-64) in the placebo arm. The grade ≥3 adverse events in the ganitumab, conatumumab, and placebo arms, respectively, included neutropenia (18/22/13%), thrombocytopenia (15/17/8%), fatigue (13/12/5%), alanine aminotransferase increase (15/5/8%), and hyperglycemia (18/2/3%). CONCLUSIONS Ganitumab combined with gemcitabine had tolerable toxicity and showed trends toward an improved 6-month survival rate and overall survival. Additional investigation into this combination is warranted. Conatumumab combined with gemcitabine showed some evidence of activity as assessed by the 6-month survival rate.

Phase III Trial of Cetuximab, Bevacizumab, and 5-Fluorouracil/Leucovorin vs. FOLFOX- Bevacizumab in Colorectal Cancer

BACKGROUND Cetuximab (C), alone or with irinotecan, demonstrates activity in irinotecan-refractory colorectal cancer (CRC). Activity of 5-fluorouracil (5-FU), leucovorin (L), and bevacizumab (B), and preliminary data of cetuximab + bevacizumab, and toxicity profiles suggests that FOLF-CB (5-FU, L, C+B) may have activity with a favorable toxicity profile as first-line therapy. METHODS Eligible patients were randomized at registration to either arm A (mFOLFOX6-B) (modified, 5-FU. L (folinic acid), oxaliplatin (O) + bevacizumab), administered days 1 and 15 of each 28-day cycle as bevacizumab 5 mg/kg, oxaliplatin 85 mg/m(2), leucovorin 400 mg/m(2), and 5-FU 400 mg/m(2) then 1200 mg/m(2)/day for 48 hours, or arm B (FOLF-CB), which included bevacizumab, leucovorin, and 5-FU as in arm A and cetuximab 400 mg/m(2) day 1 cycle 1; all other weekly cetuximab doses were 250 mg/m(2). RESULTS Two hundred forty-seven patients (arm A/arm B 124/123) were enrolled, and 239 were treated (118/121). Twelve-month progression-free survival (PFS) was 45%/32%, objective response rates (ORR) (complete response [CR] + partial response [PR]) were 52%/41%, disease control rates (CR+PR+stable disease [SD]) were 87%/83%, and median overall survival (OS) was 21/19.5 months, respectively. Grade 3-4 neutropenia was higher in arm A (28%/7%), as was grade 3 fatigue (12%/3%), and grade 3 neuropathy (11%/< 1%), whereas acneiform rash was confined to arm B. Retrospective analysis of KRAS mutational status did not demonstrate KRAS as a meaningful determinant of activity, except in arm B patients with KRAS-mutated tumors, which resulted in inferior PFS. Patient satisfaction favored the control (mFOLFOX6-B). CONCLUSION FOLF-CB was not superior to mFOLFOX6-B in terms of 12-month PFS and ORR, and was not more acceptable to patients. This trial supports the conclusion of other recently reported trials that concurrent cetuximab+bevacizumab should not be routinely used in metastatic CRC.

An Open-label, Single-arm, Phase 2 Trial of Panitumumab Plus FOLFIRI as Second-line Therapy in Patients with Metastatic Colorectal Cancer

BACKGROUND This prospective analysis evaluated the effect of tumor KRAS status on efficacy of second-line panitumumab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI). METHODS This phase 2, open-label, single-arm study enrolled patients with unresectable, measurable metastatic colorectal cancer (mCRC) after failure of first-line treatment with oxaliplatin-based chemotherapy plus bevacizumab. Patients received panitumumab 6 mg/kg plus FOLFIRI every 2 weeks until disease progression or intolerability. Tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) were performed by the investigators every 8 weeks from weeks 8-32 and every 12 weeks thereafter. KRAS status was determined by real-time polymerase chain reaction (PCR) on DNA extracted from fixed tumor sections. Efficacy endpoints included objective response rate, progression-free survival (PFS), and overall survival (OS). Safety endpoints included incidence of adverse events (AEs). Endpoints were evaluated by tumor KRAS status. RESULTS Of 116 patients enrolled, 109 patients with known tumor KRAS status received treatment; 59% had wild-type KRAS, and 41% had mutant KRAS. Fifteen patients (23%) with wild-type KRAS and 7 patients (16%) with mutant KRAS had a complete or partial response to treatment. Median PFS was 26 weeks (95% CI, 19-33 weeks) and 19 weeks (95% CI, 12-25 weeks) in the wild-type KRAS and mutant KRAS strata, respectively. Median OS was 50 weeks (95% CI, 39-76 weeks) and 31 weeks (95% CI, 23-47 weeks) in wild-type KRAS and mutant KRAS strata, respectively. Skin-related toxicities (86% of all patients) and diarrhea (74%) were the most common AEs. CONCLUSION Panitumumab plus FOLFIRI numerically improved objective response rate, PFS, and OS in favor of patients with wild-type KRAS tumors. The safety profile was consistent with panitumumab plus FOLFIRI trials in similar patient populations.

Axitinib and/or bevacizumab with modified FOLFOX‐6 as first‐line therapy for metastatic colorectal cancer: A randomized phase 2 study

In this multicenter, open‐label, randomized phase 2 trial, the authors evaluated the vascular endothelial growth factor receptor inhibitor axitinib, bevacizumab, or both in combination with chemotherapy as first‐line treatment of metastatic colorectal cancer (mCRC).

Abstract PD5-2: Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer

Background: Taselisib (GDC-0032) is a next-generation PI3K inhibitor with increased anti-tumor activity against PIK3CA mutant (MT) cancers. Taselisib is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform. Preclinical data show that taselisib has enhanced activity against PI3K alpha isoform (PIK3CA) MT breast cancer cell lines and enhanced antitumor activity when combined with letrozole. Clinical data with single-agent taselisib also showed increased tumor shrinkage in patients with PIK3CA MT breast cancer as compared to patients with PIK3CA wildtype (WT) breast cancer. Material and Methods: A Phase 1b dose escalation study was conducted with evaluation of taselisib doses ranging from 6-9 mg QD in combination with letrozole 2.5mg QD in a modified 3+3 design. A dose expansion cohort was conducted with taselisib 6 mg QD. Safety and tolerability of GDC-0032 was assessed, as well as pharmacokinetics (PK), pharmacodynamic (PD) assessment by FDG-PET, and anti-tumor activity by RECIST. Results: As of 31 January 2014, 28 patients were enrolled onto this study with the completion of dose escalation and the dose expansion cohort. No dose limiting toxicities (DLTs) were observed at either the 6 mg (n = 20) or 9 mg (n = 8) dose levels. Adverse events (AEs) assessed by the investigator as related to taselisib in ≥10% of patients (any grade) included diarrhea, nausea, stomatitis, fatigue, rash, decreased appetite, hyperglycemia, dysgeusia, mucosal inflammation, vomiting, muscle spasms, asthenia, dry mouth, dry skin, pruritus, and aspartate aminotransferase increased. Grade 3 and 4 adverse events assessed by the investigator as drug-related and occurring in greater than one patient included diarrhea (14%), hyperglycemia (7%), and mucosal inflammation (7%). No apparent PK interactions were observed between taselisib and letrozole. The median number of prior systemic therapies was six, and promising efficacy data has been observed in these heavily pretreated patients. Metabolic partial responses via FDG-PET (≥ 20% decrease in mean SUVmax) were observed in 11 out of 18 patients assessed (61%). Confirmed partial responses by RECIST have been observed at both the 6mg and 9mg taselisib dose levels. For patients with measurable disease at baseline, the overall response rate of 38% was observed in patients with PIK3CA MT breast cancer and 9% in patients with PIK3CA WT breast cancer. Updated data on safety, PD, efficacy, and biomarker correlates will be presented. Conclusions: The combination of taselisib and letrozole is a well-tolerated regimen with promising preliminary efficacy in PIK3CA MT breast cancer patients. This preliminary Ph1b clinical data is consistent with taselisib preclinical and single-agent clinical data showing increased anti-tumor activity for taselisib in PIK3CA MT breast cancer as compared to PIK3CA WT breast cancer. Taselisib is being further investigated in the neoadjuvant setting in combination with letrozole in the LORELEI study in patients with untreated hormone receptor-positive breast cancer. Citation Format: Cristina Saura, Jasgit Sachdev, Manish R Patel, Andres Cervantes, Dejan Juric, Jeffrey R Infante, Donald Richards, Sandra Sanabria, Xuyang Lu, Joseph Ware, Timothy R Wilson, Hema Parmar, Jerry Y Hsu, Mafalda Oliveira, Eric P Winer, Daniel D Von Hoff, Jose Baselga, Ian E Krop. Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD5-2.

PD-L1 Expression by Two Complementary Diagnostic Assays and mRNA In Situ Hybridization in Small Cell Lung Cancer

Introduction: Therapeutic antibodies to immune checkpoints show promising results. Programmed death‐ligand 1 (PD‐L1), an immune checkpoint ligand, blocks the cancer immunity cycle by binding the PD‐L1 receptor (programmed death 1). We investigated PD‐L1 protein expression and messenger RNA (mRNA) levels in SCLC. Methods: PD‐L1 protein expression and mRNA levels were determined by immunohistochemistry (IHC) with SP142 and Dako 28‐8 PD‐L1 antibodies and in situ hybridization in primary tumor tissue microarrays in both tumor cells and tumor‐infiltrating immune cells (TIICs) obtained from a limited‐disease SCLC cohort of 98 patients. An additional cohort of 96 tumor specimens from patients with extensive‐disease SCLC was assessed for PD‐L1 protein expression in tumor cells with Dako 28‐8 antibody only. Results: The overall prevalence of PD‐L1 protein expression in tumor cells was 16.5%. In the limited‐disease cohort, the prevalences of PD‐L1 protein expression in tumor cells with SP142 and Dako 28‐8 were 14.7% and 19.4% (tumor proportion score cutoff ≥1%) and PD‐L1 mRNA ISH expression was positive in 15.5% of tumor samples. Increased PD‐L1 protein/mRNA expression was associated with the presence of more TIICs (p < 0.05). The extensive‐disease cohort demonstrated a 14.9% positivity of PD‐L1 protein expression in tumor cells with Dako 28‐8 antibody. Conclusions: A subset of SCLCs is characterized by positive PD‐L1 and/or mRNA expression in tumor cells. Higher PD‐L1 and mRNA expression correlate with more infiltration of TIICs. The prevalence of PD‐L1 in SCLC is lower than that published for NSCLC. The predictive role of PD‐L1 expression in SCLC treatment remains to be established.

Eltrombopag with gemcitabine-based chemotherapy in patients with advanced solid tumors: a randomized phase I study

Preventing chemotherapy‐induced thrombocytopenia could avoid chemotherapy dose reductions and delays. The safety and maximum tolerated dose of eltrombopag, an oral thrombopoietin receptor agonist, with gemcitabine‐based therapy was evaluated. Patients with advanced solid tumors and platelets ≤300 × 109/L receiving gemcitabine plus cisplatin or carboplatin (Group A) or gemcitabine monotherapy (Group B) were randomized 3:1 to receive eltrombopag or placebo at a starting dose of 100 mg daily administered on days −5 to −1 and days 2–6 starting from cycle 2 of treatment. Nineteen patients (Group A, n = 9; Group B, n = 10) received eltrombopag 100 mg and seven (Group A, n = 3; Group B, n = 4) received matching placebo. Nine eltrombopag patients in Group A and eight in Group B had 38 and 54 occurrences of platelet counts ≥400 × 109/L, respectively. Mean platelet nadirs across cycles 2–6 were 115 × 109/L and 143 × 109/L for eltrombopag‐treated patients versus 53 × 109/L and 103 × 109/L for placebo‐treated patients in Groups A and B, respectively. No dose‐limiting toxicities were reported for eltrombopag; however, due to several occurrences of thrombocytosis, a decision was made not to dose‐escalate eltrombopag to >100 mg daily. In Groups A and B, 14% of eltrombopag versus 50% of placebo patients required chemotherapy dose reductions and/or delays for any reason across cycles 3–6. Eltrombopag 100 mg once daily administered 5 days before and after day 1 of chemotherapy was well tolerated with an acceptable safety profile, and will be further tested in a phase II trial. Fewer patients receiving eltrombopag required chemotherapy dose delays and/or reductions compared with those receiving placebo.

Safety, tolerability, and preliminary activity of LB-100, an inhibitor of protein phosphatase 2A, in patients with relapsed solid tumors: An open-label, dose escalation, first-in-human, phase I trial

Purpose: To determine the MTD and to assess the safety, tolerability, and potential activity of LB-100, a first-in-class small-molecule inhibitor of protein phosphatase 2A (PP2A) in adult patients with progressive solid tumors. Experimental Design: LB-100 was administered intravenously daily for 3 days in 21-day cycles in a 3 + 3 dose escalation design. Results: There were 29 patient entries over 7 dose escalations. One patient stopped treatment after one dose because of an acute infection and was reenrolled after recovery; each course was analyzed as a separate patient entry. Two patients had dose-limiting toxicity (reversible increases in serum creatinine or calculated serum creatinine clearance) at the 3.1 mg/m2 level. Probable or possible study drug-related grade 3 adverse events occurred in 6 (20.7%) patients [anemia (n = 2), decreased creatinine clearance, dyspnea, hyponatremia, and lymphopenia]. Ten (50%) of 20 response-evaluable patients had stable disease for four or more cycles. One patient with pancreatic adenocarcinoma had a partial response noted after 10 cycles, which was maintained for five additional cycles. The other patients achieving stable disease had one of the following: fibrosarcoma, chondrosarcoma, thymoma, atypical carcinoid of lung, or ovarian, testicular, breast (n = 2), and prostate cancer. The recommended phase II dose of LB-100 is 2.33 mg/m2 daily for 3 days every 3 weeks. Conclusions: The safety, tolerability, preliminary evidence of antitumor activity, and novel mechanism of action of LB-100 support its continued development alone and in combination with other therapies. Clin Cancer Res; 23(13); 3277–84. ©2016 AACR.