3+7 Combined Chemotherapy for Acute Myeloid Leukemia: Is It Time to Say Goodbye?

Purpose Of Review: With the recent approval of multiple new drugs for the treatment of acute myeloid leukemia (AML), the relevance of conventional treatment approaches, such as daunorubicin and cytarabine ("3+7") induction chemotherapy, has been challenged. We review the AML risk stratification, the efficacy of the newly approved drugs, and the role of "3+7".

Recent Findings: Treatment of AML is becoming more niched with specific subtypes more appropriately treated with gemtuzumab, midostaurin, and CPX-351.

A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer.

Background: This phase I, four-arm, open-label study (NCT01347866) evaluated the PI3K/mTOR inhibitors PF-04691502 (arms A, B) and gedatolisib (PF-05212384; arms C, D) in combination with the MEK inhibitor PD-0325901 (arm A, D) or irinotecan (arm B, C) in patients with advanced solid tumors.

Objectives: Primary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity.

The differential effects of metronomic gemcitabine and antiangiogenic treatment in patient-derived xenografts of pancreatic cancer: treatment effects on metabolism, vascular function, cell proliferation, and tumor growth.

Background: Metronomic chemotherapy has shown promising activity against solid tumors and is believed to act in an antiangiogenic manner. The current study describes and quantifies the therapeutic efficacy, and mode of activity, of metronomic gemcitabine and a dedicated antiangiogenic agent (DC101) in patient-derived xenografts of pancreatic cancer.

Methods: Two primary human pancreatic cancer xenograft lines were dosed metronomically with gemcitabine or DC101 weekly.

Investigation of the 4D composite MR image distortion field associated with tumor motion for MR-guided radiotherapy.

Purpose: Magnetic resonance (MR) images are affected by geometric distortions due to the specifics of the MR scanner and patient anatomy. Quantifying the distortions associated with mobile tumors is particularly challenging due to real anatomical changes in the tumor's volume, shape, and relative location within the MR imaging volume. In this study, the authors investigate the 4D composite distortion field, which combines the effects of the susceptibility-induced and system-related distortion fields, experienced by mobile lung tumors.

Bevacizumab, temozolomide, and radiotherapy for newly diagnosed glioblastoma: comprehensive safety results during and after first-line therapy.

Background: The proposed use of bevacizumab with radiotherapy/temozolomide for newly diagnosed glioblastoma raised potential safety concerns. Bevacizumab has been linked with stroke, bleeding events, and wound-healing complications in other tumor types; these events are of particular concern for glioblastoma (highly vascular tumors that are usually resected). Published data on the interaction of bevacizumab with radiotherapy/temozolomide are also limited.

A phase I trial of ANG1/2-Tie2 inhibitor trebaninib (AMG386) and temsirolimus in advanced solid tumors (PJC008/NCI♯9041).

Background: There is crosstalk between the ANG-Tie2 and the PI3K/Akt/mTOR pathways. Combined ANG1/2 and mTOR blockade may have additive anti-cancer activity. The combination of trebananib, an inhibitor of ANG1/2-Tie2 interaction, with temsirolimus was evaluated in patients with advanced solid tumors to determine tolerability, maximum tolerated dose (MTD), and preliminary antitumor activity.

Development of peripheral neuropathy and its association with survival during treatment with nab-paclitaxel plus gemcitabine for patients with metastatic adenocarcinoma of the pancreas: A subset analysis from a randomised phase III trial (MPACT).

Background: In a phase III trial in patients with metastatic pancreatic cancer (MPC), nab-paclitaxel plus gemcitabine (nab-P/Gem) demonstrated greater efficacy but higher rates of peripheral neuropathy (PN) versus Gem. This exploratory analysis aimed to characterise the frequency, duration, and severity of PN with nab-P/Gem in the MPACT study.

Patients And Methods: Patients with previously untreated MPC received nab-P/Gem or Gem.

Synergistic action of image-guided radiotherapy and androgen deprivation therapy.

The combined use of androgen deprivation therapy (ADT) and image-guided radiotherapy (IGRT) can improve overall survival in aggressive, localized prostate cancer. However, owing to the adverse effects of prolonged ADT, it is imperative to identify the patients who would benefit from this combined-modality therapy relative to the use of IGRT alone. Opportunities exist for more personalized approaches in treating aggressive, locally advanced prostate cancer.

Dose escalation to rash for erlotinib plus gemcitabine for metastatic pancreatic cancer: the phase II RACHEL study.

Background: This phase II, open-label, randomised study evaluated whether patients with metastatic pancreatic cancer receiving erlotinib/gemcitabine derived survival benefits from increasing the erlotinib dose.

Methods: After a 4-week run-in period (gemcitabine 1000 mg m(-2) once weekly plus erlotinib 100 mg per day), patients with metastatic pancreatic cancer who developed grade 0/1 rash were randomised to receive gemcitabine plus erlotinib dose escalation (150 mg, increasing by 50 mg every 2 weeks (maximum 250 mg); n=71) or gemcitabine plus standard-dose erlotinib (100 mg per day; n=75). The primary end point was to determine whether overall survival (OS) was improved by increasing the erlotinib dose.

Does change in health-related quality of life score predict survival? Analysis of EORTC 08975 lung cancer trial.

Background: Little is known about whether changes in health-related quality of life (HRQoL) scores from baseline during treatment also predict survival, which we aim to investigate in this study.

Methods: We analysed data from 391 advanced non-small-cell lung cancer (NSCLC) patients enrolled in the EORTC 08975 study, which compared palliative chemotherapy regimens. HRQoL was assessed at baseline and after each chemotherapy cycle using the EORTC QLQ-C30 and QLQ-LC13.

Conditional probability of survival and post-progression survival in patients with glioblastoma in the temozolomide treatment era.

With standard treatment for glioblastoma (GBM) consisting of surgery followed by radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ), median survival is ~14.6 months. This is not as informative to patients who have survived for some time.

A phase II multicentre study of ziv-aflibercept in combination with cisplatin and pemetrexed in patients with previously untreated advanced/metastatic non-squamous non-small cell lung cancer.

Background: This study evaluated the efficacy and safety of ziv-aflibercept in combination with cisplatin and pemetrexed in non-small cell lung cancer (NSCLC).

Methods: This single arm, multicentre phase II trial enrolled patients with previously untreated, locally advanced or metastatic non-squamous NSCLC. Patients received intravenous ziv-aflibercept 6 mg kg(-1), pemetrexed 500 mg m(-2), and cisplatin 75 mg m(-2), every 21 days for up to six cycles.

Glioblastoma management in the temozolomide era: have we improved outcome?

Temozolomide (TMZ) during and after radiotherapy (RT) is recommended for patients with newly diagnosed glioblastoma (GBM). We analyzed the adoption of this new standard of care for GBM in an academic cancer centre in Canada and assessed its impact on survival. GBM patients registered with Cancer Care Ontario between 2004 and 2008 were identified.

Current phase II clinical data for ridaforolimus in cancer.

Introduction: The PI3K/AKT/mammalian target of rapamycin (mTOR) pathway plays a critical role in controlling cellular metabolism, proliferation and cell cycle regulation. Constitutive activation of this pathway has been demonstrated in many tumor types. Targeting the PI3K/AKT/mTOR pathway is of increasing therapeutic interest.

A phase Ib combination study of RO4929097, a gamma-secretase inhibitor, and temsirolimus in patients with advanced solid tumors.

Background: To determine the recommended phase II dose (RP2D) and assess the safety, pharmacokinetics (PKs) and pharmacodynamics of RO4929097in combination with temsirolimus.

Methods: Escalating doses of RO4929097 and temsirolimus were administered at three dose levels. Patients received once daily oral RO4929097 on a 3 days on/4 days off schedule every week, and weekly intravenous temsirolimus.

A phase I study of the oral gamma secretase inhibitor R04929097 in combination with gemcitabine in patients with advanced solid tumors (PHL-078/CTEP 8575).

Purpose: To establish the recommended phase II dose of the oral γ-secretase inhibitor RO4929097 (RO) in combination with gemcitabine; secondary objectives include the evaluation of safety, tolerability, pharmacokinetics, biomarkers of Notch signaling and preliminary anti-tumor activity.

Methods: Patients with advanced solid tumors were enrolled in cohorts of escalating RO dose levels (DLs). Tested RO DLs were 20 mg, 30 mg, 45 mg and 90 mg.

In vivo RAF signal transduction as a potential biomarker for sorafenib efficacy in patients with neuroendocrine tumours.

Background: Targeted therapies elicit anticancer activity by exerting pharmacodynamic effects on specific molecular targets. Currently, there is limited use of pharmacodynamic assessment to guide drug administration in the routine oncology setting.

Methods: We developed a phosphoshift (pShift) flow cytometry-based test that measures RAF signal transduction capacity in peripheral blood cells, and evaluated it in a phase II clinical trial of oral sorafenib plus low-dose cyclophosphamide in patients with advanced neuroendocrine tumours (NETs), in order to predict clinical course and/or guide individual dose-titration.

Lenalidomide alone and in combination for chronic lymphocytic leukemia.

Lenalidomide is a member of the immunomodulatory agents (IMiDs), and is currently approved for use in myelodysplastic syndromes and multiple myeloma. In chronic lymphocytic leukemia (CLL), lenalidomide has anti-tumor activity which appears distinct, both mechanistically and clinically, from that observed in the approved indications. Furthermore, lenalidomide leads to toxicities, such as tumor flare reaction and tumor lysis, even at low dosing, that is not anticipated with lenalidomide therapy in other disorders.

A phase I dose-escalation study of aflibercept administered in combination with pemetrexed and cisplatin in patients with advanced solid tumours.

Background: To evaluate the safety, pharmacokinetics (PKs), and pharmacodynamics of aflibercept, and to identify the recommended phase II dose (RP2D) of aflibercept in combination with pemetrexed and cisplatin.

Methods: Aflibercept was administered at escalating doses of 2, 4, or 6 mg kg(-1) in combination with fixed doses of pemetrexed (500 mg m(-2)) plus cisplatin (75 mg m(-2)) every 3 weeks. Blood samples were collected for PK analyses.

A phase I study of temozolomide and everolimus (RAD001) in patients with newly diagnosed and progressive glioblastoma either receiving or not receiving enzyme-inducing anticonvulsants: an NCIC CTG study.

Purpose: This phase I trial was designed to determine the recommended phase II dose(s) of everolimus (RAD001) with temozolomide (TMZ) in patients with glioblastoma (GBM). Patients receiving enzyme-inducing antiepileptic drugs (EIAEDs) and those not receiving EIAEDs (NEIAEDs) were studied separately.

Patients And Methods: Enrollment was restricted to patients with proven GBM, either newly diagnosed or at first progression.

A Phase II trial of erlotinib as maintenance treatment after gemcitabine plus platinum-based chemotherapy in patients with recurrent and/or metastatic nasopharyngeal carcinoma.

Background: Despite the efficacy of gemcitabine-platinum regimen, the outcome of patients with recurrent and/or metastatic nasopharyngeal carcinoma (RM NPC) is poor. A phase II trial was conducted to determine the efficacy of erlotinib, given as maintenance therapy after gemcitabine-platinum chemotherapy in patients with RM NPC.

Patients And Methods: Patients were treated with gemcitabine 1000 mg/m on days 1 and 8 as well as cisplatin 70 mg/m on day 1 (or carboplatin area under curve 5 on day 1, if contraindication to cisplatin) 3 weeks.

A phase I/II study of the Src inhibitor saracatinib (AZD0530) in combination with gemcitabine in advanced pancreatic cancer.

Aim: This phase I/II study of saracatinib in combination with gemcitabine in patients with advanced pancreatic cancer was conducted by the NCIC Clinical Trials Group. The aims were to define the recommended phase II dose (RP2D) of saracatinib when combined with gemcitabine, and assess the efficacy of this combination in advanced pancreatic cancer.

Patients And Methods: Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and no prior chemotherapy.

Evolution of systemic therapy for advanced pancreatic cancer.

The prognosis for advanced pancreatic cancer remains poor and successful drug development in this disease continues to be a major challenge. In the last decade the approach to drug development in pancreatic cancer has included a focus on combinations of cytotoxic agents. While some promising results were seen in Phase II studies, none of the Phase III trials of cytotoxic combinations were able to demonstrate an improvement in overall survival over that seen with the single-agent gemcitabine.

A phase II trial of sorafenib in first-line metastatic urothelial cancer: a study of the PMH Phase II Consortium.

Background: Sorafenib is an oral multikinase inhibitor that blocks cell proliferation via the ERK pathway and angiogenesis via the VEGF pathway. This phase II trial was conducted to determine the efficacy and tolerability of sorafenib for the treatment of patients with metastatic urothelial cancer (UC) who had not had prior chemotherapy for advanced disease.

Patients And Methods: Seventeen chemo-naïve UC patients with adequate performance status and organ function were treated with sorafenib 400 mg twice daily on a continuous basis until progression or unacceptable toxicity.