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1.
Future Oncol ; 17(21): 2747-2758, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33849298

ABSTRACT

Aim: This Phase I study investigated safety of navitoclax and docetaxel in patients (n = 41) with advanced solid tumors. Patients & methods: Two navitoclax plus docetaxel dosing schedules (21 and 28 days) were evaluated. Maximum tolerated dose, dose-limiting toxicities and preliminary antitumor activity were assessed. Results: Ten (24%) patients experienced dose-limiting toxicities; dose-escalation cohorts: n = 7 (21-day schedule: n = 5; 28-day schedule: n = 2) and 21-day expanded safety cohort: n = 3. Navitoclax 150-mg days 1-5 every 21 days with docetaxel 75 mg/m2 day 1 was the maximum tolerated dose and optimal schedule. Adverse events included thrombocytopenia (63%), fatigue (61%), nausea (59%) and neutropenia (51%). Four confirmed partial responses occurred. Conclusion: Navitoclax 150-mg orally once/day was safely administered with docetaxel. Myelosuppression limited dose escalation; antitumor activity was observed. Clinical trial registration: NCT00888108 (ClinicalTrials.gov).


Subject(s)
Aniline Compounds/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Docetaxel/adverse effects , Neoplasms/drug therapy , Sulfonamides/adverse effects , Administration, Oral , Adult , Aged , Aged, 80 and over , Aniline Compounds/administration & dosage , Aniline Compounds/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Docetaxel/administration & dosage , Docetaxel/pharmacokinetics , Drug Administration Schedule , Fatigue/chemically induced , Fatigue/epidemiology , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Nausea/chemically induced , Nausea/epidemiology , Neutropenia/chemically induced , Neutropenia/epidemiology , Sulfonamides/administration & dosage , Sulfonamides/pharmacokinetics , Thrombocytopenia/chemically induced , Thrombocytopenia/epidemiology
2.
Clin Cancer Res ; 25(13): 3830-3838, 2019 07 01.
Article in English | MEDLINE | ID: mdl-30952636

ABSTRACT

PURPOSE: Anti-EGFR mAbs are effective in the treatment of metastatic colorectal cancer (mCRC) patients. RAS status and tumor location (sidedness) are predictive markers of patients' response to anti-EGFR mAbs. Recently, low miR-31-3p expression levels have been correlated with clinical benefit from the anti-EGFR mAb cetuximab. Here, we aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemorefractory mCRC patients treated with single-agent anti-EGFR mAbs. EXPERIMENTAL DESIGN: miR-31-3p was tested by in situ hybridization (ISH) in 91 pretreatment core biopsies from metastatic deposits of 45 patients with mCRC. Sequential tissue biopsies obtained before treatment, at the time of partial response, and at disease progression were tested to monitor changes in miR-31-3p expression overtreatment. miR-31-3p expression, sidedness, and RAS status in pretreatment cell-free DNA were combined in multivariable regression models to assess the predictive value of each variable alone or in combination. RESULTS: Patients with low miR-31-3p expression in pretreatment biopsies showed better overall response rate, as well as better progression-free survival and overall survival, compared to those with high miR-31-3p expression. The prognostic effect of miR-31-3p was independent from age, gender, and sidedness. No significant changes in the expression of miR-31-3p were observed when sequential tissue biopsies were tested in long-term or poor responders to anti-EGFR mAbs. miR-31-3p scores were similar when pretreatment biopsies were compared with treatment-naïve archival tissues (often primary colorectal cancer). CONCLUSIONS: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mAbs.


Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Gene Expression , MicroRNAs/genetics , Aged , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Colorectal Neoplasms/diagnosis , Colorectal Neoplasms/mortality , ErbB Receptors/antagonists & inhibitors , ErbB Receptors/metabolism , Female , Humans , Immunohistochemistry , In Situ Hybridization , Male , Middle Aged , Molecular Targeted Therapy , Prognosis , Retreatment , Tomography, X-Ray Computed , Treatment Outcome
3.
Cancer Discov ; 8(10): 1270-1285, 2018 10.
Article in English | MEDLINE | ID: mdl-30166348

ABSTRACT

Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in RAS wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as RAS wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies.Significance: Liquid biopsies capture spatial and temporal heterogeneity underpinning resistance to anti-EGFR monoclonal antibodies in colorectal cancer. Dense serial sampling is needed to predict the time to treatment failure and generate a window of opportunity for intervention. Cancer Discov; 8(10); 1270-85. ©2018 AACR. See related commentary by Siravegna and Corcoran, p. 1213 This article is highlighted in the In This Issue feature, p. 1195.


Subject(s)
Colorectal Neoplasms/diagnosis , Liquid Biopsy/methods , Adult , Aged , Aged, 80 and over , Clinical Trials as Topic , Clonal Evolution , Colorectal Neoplasms/pathology , Female , Humans , Male , Middle Aged , Models, Theoretical , Time-to-Treatment , Treatment Failure
4.
Oncologist ; 21(7): 855-60, 2016 07.
Article in English | MEDLINE | ID: mdl-27151652

ABSTRACT

BACKGROUND: Dysregulation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway is implicated in human cancer growth and progression. Agents targeting this pathway are associated with hyperglycemia due to interaction with the insulin-glucose regulatory axis. Identifying the predictive factors for hyperglycemia in patients treated with these agents may help direct future management. MATERIALS AND METHODS: Clinical characteristics and outcomes of patients treated consecutively with PI3K, AKT, or mTOR inhibitors in the Drug Development Unit, The Royal Marsden (RM) National Health Service (NHS) Foundation Trust, between 2007 and 2012 were recorded. Baseline variables and their association with grade 3 hyperglycemia (Common Terminology Criteria for Adverse Events, version 3.0) were analyzed by using the chi-square test and Fisher exact test for categorical variables and binary logistic regression for continuous variables. RESULTS: A total of 341 patients were treated in 12 phase I trials of PI3K/AKT/mTOR inhibitors, and 298 patients (87.4%) developed hyperglycemia. Hyperglycemia was grade 1 in 217 (72.8%) and grade 2 in 61 (20.5%) patients, respectively. Grade ≥3 hyperglycemia was seen in 6.7% of patients (n = 20). According to the chi-square test, age <65 years (p = .03), history of diabetes (p = .003), and treatment with AKT and dual PI3K/mTOR inhibitors (p < .0005) predicted the occurrence of grade 3 hyperglycemia. Of 24 patients requiring intervention, 20 received metformin, 2 dietary advice, 1 insulin, and 1 both metformin and insulin. One patient required dose reduction. There were no permanent drug discontinuations, and no hyperglycemia-related dose-limiting toxicities were observed; thus, the recommended phase II dose was not affected by the hyperglycemia observed in our cohort. CONCLUSION: Hyperglycemia is common in patients treated with PI3K/AKT/mTOR inhibitors; however, it is manageable with conventional treatment. Predictive factors of age, history of diabetes, and administration of AKT and dual PI3K/mTOR inhibitors warrant prospective validation. IMPLICATIONS FOR PRACTICE: This study reviewed the clinical data of 341 patients treated in 12 phase I trials of agents targeting phosphatidylinositol3-kinase (PI3), protein kinase B (AKT), and mammalian target of rapamycin (mTOR), as well as dual inhibitors. Hyperglycemia was evident in 87.4% of patients but was ≥grade 3 in just 6.7%. Age <65 years, history of diabetes, and treatment with AKT and dual PI3K/mTOR inhibitors were each associated with grade 3 hyperglycemia. Management of patients was uncomplicated, and no permanent drug discontinuations were necessary. Despite the small study size, these findings support continued caution about enrolling patients with a history of diabetes into such trials. However, clinicians may be reassured, pending prospective validation of these results, that significant hyperglycemia is not frequent and, when it occurs, is manageable.


Subject(s)
Hyperglycemia/chemically induced , Neoplasms/drug therapy , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/adverse effects , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adult , Aged , Female , Humans , Male , Middle Aged , Retrospective Studies
5.
Crit Rev Oncol Hematol ; 90(3): 200-19, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24507955

ABSTRACT

Apoptosis, a physiological process of programmed cell death, is disrupted in various malignancies. It has been exploited as an anti-cancer strategy traditionally by inducing DNA damage with chemotherapy and radiotherapy. With an increased understanding of the intrinsic and extrinsic pathways of apoptosis in recent years, novel approaches of targeting the apoptotic pathways have been tested in pre-clinical and clinical models. There are several early phase clinical trials investigating the therapeutic role of pro-apoptotic agents, both as single agents and in combination. In this review, we examine such treatment strategies, detailing the various compounds currently under clinical investigation, their potential roles in cancer therapeutics, and discussing approaches to their optimal use in the clinic.


Subject(s)
Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Neoplasms/drug therapy , Neoplasms/metabolism , Signal Transduction/drug effects , Animals , Biomarkers/metabolism , Humans , Molecular Targeted Therapy
6.
Chin J Cancer ; 32(5): 253-65, 2013 May.
Article in English | MEDLINE | ID: mdl-23642907

ABSTRACT

The phosphoinositide 3-kinase-AKT-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway is a frequently hyperactivated pathway in cancer and is important for tumor cell growth and survival. The development of targeted therapies against mTOR, a vital substrate along this pathway, led to the approval of allosteric inhibitors, including everolimus and temsirolimus, for the treatment of breast, renal, and pancreatic cancers. However, the suboptimal duration of response in unselected patients remains an unresolved issue. Numerous novel therapies against critical nodes of this pathway are therefore being actively investigated in the clinic in multiple tumor types. In this review, we focus on the progress of these agents in clinical development along with their biological rationale, the need of predictive biomarkers and various combination strategies, which will be useful in counteracting the mechanisms of resistance to this class of drugs.


Subject(s)
Neoplasms/metabolism , Phosphoinositide-3 Kinase Inhibitors , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , TOR Serine-Threonine Kinases/antagonists & inhibitors , Antineoplastic Agents/therapeutic use , Drug Resistance, Neoplasm , Humans , Molecular Targeted Therapy , Neoplasms/drug therapy , Neoplasms/genetics , PTEN Phosphohydrolase/genetics , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Proto-Oncogene Proteins c-ret/metabolism , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/metabolism
7.
Tumori ; 98(5): 575-80, 2012.
Article in English | MEDLINE | ID: mdl-23235751

ABSTRACT

AIMS AND BACKGROUND: . The incidence of malignant melanoma has risen steadily over recent decades. NCI data from 2005-2007 have suggested that 1.93% of individuals born today in the US will develop melanoma at some stage. Approximately 15% of patients with MM either present with metastatic disease or develop metastases during the course of their illness. Unfortunately, metastatic MM remains a challenge with limited treatment options, and median overall survival is 6-9 months. METHODS: We reviewed our data for the treatment of metastatic MM over a period of four years. Data from all patients with metastatic MM treated with systemic therapy without clinical trials from 2006 to 2009 were reviewed. Response rate was determined as per RECIST criteria. RESULTS: Sixty four patients were treated with one or more lines of cytotoxic therapy. Median age was 62 years (range, 23-82) with 53% males. Primary site of the disease was the skin in 75%, mucosal in 12.5%, ocular in 9.4% and nodal with an occult primary in 3.1%. Visceral metastases were present in 75% of patients at the start of treatment, including pulmonary (39.6%) and hepatic (34.4%). All patients were screened for brain metastases, which were present in 26.5% of patients. ECOG performance status was 0 in 7.8%, 1 in 68.7%, 2 in 9.4% and undocumented in the remaining 14%. Patients without brain metastases received single agent DTIC as first line; those with brain metastases received temozolomide. Response rate was 7% for DTIC and 28% for temozolomide, with median progression-free survival of 2.4 and 3.2 months, respectively. Seven patients who received DTIC are alive on follow-up, 2 have ongoing stable disease post-DTIC at 41 months and 18 months. Second line therapy with vinblastine was given to 21 patients (32%), with a response rate of 9.5% and median progression-free survival of 3.4 months. Median overall survival from initiation of therapy was 7.7 months for DTIC and 3.6 months for patients with brain metastases receiving temozolomide. A performance status of 2 was associated with shorter median overall survival (2.0 months). CONCLUSIONS: . Our results are comparable to published data. Malignant melanoma is a disease with rising incidence and limited treatment options. These patients are best treated in the context of clinical trials as new targeted therapies are promising as future strategies.


Subject(s)
Antineoplastic Agents/therapeutic use , Melanoma/drug therapy , Melanoma/secondary , Skin Neoplasms/drug therapy , Skin Neoplasms/pathology , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal/administration & dosage , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Brain Neoplasms/secondary , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/metabolism , Clinical Trials as Topic , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Disease Progression , Disease-Free Survival , Female , Humans , Incidence , Interleukin-2/administration & dosage , Ipilimumab , Lymphatic Metastasis , Male , Melanoma/metabolism , Melanoma/mortality , Middle Aged , Mutation , Prevalence , Proto-Oncogene Proteins B-raf/genetics , Retrospective Studies , Skin Neoplasms/metabolism , Skin Neoplasms/mortality , Temozolomide , Treatment Outcome , Vinblastine/administration & dosage
9.
Ulster Med J ; 76(3): 144-5, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17853640

ABSTRACT

AIMS: To investigate the impact of fertility control efforts on reducing fertility and to study the contributory role of fertility inhibiting factors viz, age of the marriage, breast feeding and post-partum amenorrhea, abortion and use of contraceptives in selected area in Karachi, Pakistan. The aim was to estimate the gap between knowledge of contraceptives and its practice i.e. KAP-GAP as well as to determine the level of unmet need in the PIB colony in Karachi. DATA SOURCE: A sample survey was conducted in PIB colony in Karachi from October 2005 to November 2005 by interviewing 340 married women in reproductive ages. The data was tabulated and John Bongaarts technique was used to analyse the success of fertility control efforts in the selected area. RESULTS: Of the total of 340 respondents, 38% were currently using contraceptive methods with 26% using OCP's and 12% were condom users. A slight reduction in total fertility (TFR) was noticed. CONCLUSION: The population policy of Pakistan envisages achieving population stabilization in 2020 by reducing the annual rate of population growth from 1.9% to 1.3% and TFR at 2.1. This target requires strenuous efforts to make the concept of small family an accepted milieu through an eagerly designed communication and education campaign. Concentration on proximate determinants of fertility particularly breast feeding and prolonging birth interval will not generate opposition from the community because these concepts are in accordance with Islamic injunctions and teachings.


Subject(s)
Family Planning Services/organization & administration , Fertility , Population Control , Population Density , Reproductive Health Services/organization & administration , Adolescent , Adult , Contraception , Contraceptive Agents , Female , Health Care Surveys , Health Policy , Humans , Middle Aged , Pakistan , Pilot Projects , Social Marketing
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