Donald K Strickland

Late Effects of Treatment in Survivors of Childhood Acute Myeloid Leukemia

PURPOSE To investigate the incidence of and risk factors for late sequelae of treatment in patients who survived for more than 10 years after the diagnosis of childhood acute myeloid leukemia (AML). PATIENTS AND METHODS Of 77 survivors (median follow-up duration, 16. 7 years), 44 (group A) had received chemotherapy, 18 (group B) had received chemotherapy and cranial irradiation, and 15 (group C) had received chemotherapy, total-body irradiation, and allogeneic bone marrow transplantation. Late complications, tobacco use, and health insurance status were assessed. RESULTS Growth abnormalities were found in 51% of survivors, neurocognitive abnormalities in 30%, transfusion-acquired hepatitis in 28%, endocrine abnormalities in 16%, cataracts in 12%, and cardiac abnormalities in 8%. Younger age at the time of diagnosis or initiation of radiation therapy, higher dose of radiation, and treatment in groups B and C were risk factors for the development of academic difficulties and greater decrease in height Z: score. In addition, treatment in group C was a risk factor for a greater decrease in weight Z: score and the development of growth-hormone deficiency, hypothyroidism, hypogonadism, infertility, and cataracts. The estimated cumulative risk of a second malignancy at 20 years after diagnosis was 1.8% (95% confidence interval, 0.3% to 11.8%). Twenty-two patients (29%) were smokers, and 11 (14%) had no medical insurance at the time of last follow-up. CONCLUSION Late sequelae are common in long-term survivors of childhood AML. Our findings should be useful in defining areas for surveillance of and intervention for late sequelae and in assessing the risk of individual late effects on the basis of age and history of treatment.

Rovalpituzumab tesirine, a DLL3-targeted antibody-drug conjugate, in recurrent small-cell lung cancer: a first-in-human, first-in-class, open-label, phase 1 study

BACKGROUND Rovalpituzumab tesirine is a first-in-class antibody-drug conjugate directed against delta-like protein 3 (DLL3), a novel target identified in tumour-initiating cells and expressed in more than 80% of patients with small-cell lung cancer. We aimed to assess the safety and activity of rovalpituzumab tesirine in patients who progressed after one or more previous regimen. METHODS We conducted a phase 1 open-label study at ten cancer centres in the USA. Eligible patients were aged 18 years or older and had histologically or cytologically confirmed small-cell lung cancer or large-cell neuroendocrine tumours with progressive measurable disease (according to Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) previously treated with one or two chemotherapeutic regimens, including a platinum-based regimen. We assigned patients to dose-escalation or expansion cohorts, ranging from 0·05 mg/kg to 0·8 mg/kg rovalpituzumab tesirine intravenously every 3 weeks or every 6 weeks, followed by investigation of the dose schedules 0·3 mg/kg and 0·4 mg/kg every 6 weeks and 0·2 mg/kg every 3 weeks. Primary objectives were to assess the safety of rovalpituzumab tesirine, including the maximum tolerated dose and dose-limiting toxic effects. The primary activity endpoint was objective response by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, number NCT01901653. The study is closed to enrolment; this report focuses on the cohort with small-cell lung cancer. FINDINGS Between July 22, 2013, and Aug 10, 2015, 82 patients were enrolled, including 74 patients with small-cell lung cancer and eight with large-cell neuroendocrine carcinoma, all of whom received at least one dose of rovalpituzumab tesirine. Dose-limiting toxic effects of rovalpituzumab tesirine occurred at a dose of 0·8 mg/kg every 3 weeks, including grade 4 thrombocytopenia (in two of two patients at that dose level) and grade 4 liver function test abnormalities (in one patient). The most frequent grade 3 or worse treatment-related adverse events in 74 patients with small-cell lung cancer were thrombocytopenia (eight [11%]), pleural effusion (six [8%]), and increased lipase (five [7%]). Drug-related serious adverse events occurred in 28 (38%) of 74 patients. The maximum tolerated dose of rovalpituzumab tesirine was 0·4 mg/kg every 3 weeks; the recommended phase 2 dose and schedule is 0·3 mg/kg every 6 weeks. At active doses of rovalpituzumab tesirine (0·2 mg/kg or 0·4 mg/kg every 3 weeks or 0·3 mg/kg or 0·4 mg/kg every 6 weeks), 11 (18%) of 60 assessable patients had a confirmed objective response. 11 (18%) of 60 assessable patients had a confirmed objective response, including ten (38%) of 26 patients confirmed to have high DLL3 expression (expression in 50% or more of tumour cells). INTERPRETATION Rovalpituzumab tesirine shows encouraging single-agent antitumour activity with a manageable safety profile. Further development of rovalpituzumab tesirine in DLL3-expressing malignant diseases is warranted. FUNDING Stemcentrx Inc.

Hepatitis C infection and hepatocellular carcinoma after treatment of childhood cancer

The results of preliminary reports of childhood cancer survivors with hepatitis C infection (HCV) show that in none of these patients did the disease progress to liver failure or hepatocellular carcinoma (HCC). The authors describe two patients who were diagnosed with HCC more than 20 years after the treatment of childhood acute lymphocytic leukemia. Serologic testing, done at the time HCC was diagnosed, found HCV-directed antibodies, suggesting that chronic HCV infection contributed to the development of the subsequent neoplasm. Identification of infected patients will permit intervention to reduce the risk of progressive liver disease and will also assist in defining the risk of and variables contributing to progressive liver disease.

ORAL02.01: Safety and Efficacy of Single-Agent Rovalpituzumab Tesirine, a DLL3-Targeted ADC, in Recurrent or Refractory SCLC: Topic: Medical Oncology

All Treated Patients (TC2/3 or IC2/3) Cohort 1 (1L) 139 24% (17-32) 7.3 (5.6-9.1) 20.1 (20.1-NE) Cohort 2 (2L) 268 19% (15-24) 2.8 (2.6-4.1) 15.5 (12.3-NE) Cohort 3 (3L+) 252 19% (15-25) 3.0 (2.8-4.1) 13.2 (10.3-17.5) PD-L1 TC3 or IC3 Subgroup Cohort 1 (1L) 65 32% (21-45) 7.3 (4.9-12.0) NE (12.0-NE) Cohort 2 (2L) 122 25% (18-34) 4.1 (2.6-6.5) 15.1 (12.0-NE) Cohort 3 (3L+) 115 30% (22-39) 4.2 (3.0-6.2) 17.5 (11.1-NE)

Abstract CT233: A phase I study evaluating continuous and intermittent AZD2014 in combination with fulvestrant in patients with ER+ advanced metastatic breast cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Preclinical and clinical (BOLERO 2) data suggest that pts with ER+ breast cancer become less sensitive to hormonal therapy over time with greater dependency on the mTOR pathway. AZD2014 is a selective dual mTORC1 and mTORC2 inhibitor that may offer additional benefit vs mTORC1 inhibitors through suppression of AKT via mTORC2. Preclinical data demonstrate that continuous or intermittent dosing schedules are equally effective in a model of ER+ breast cancer and the latter may achieve improved tolerability in pts. This Ph I trial assesses the safety, tolerability, PK, PD and preliminary efficacy of AZD2014 administered both continuously and intermittently in combination with fulvestrant (F); data are unvalidated and subject to change. Methods: Adult pts with ER+ metastatic breast cancer were treated with continuous or intermittent AZD2014 in combination with F 500mg intramuscularly on day 1 of each 28 day cycle. Results: In the continuous schedules, 43 pts have been treated in 4 cohorts: 50mg BD = 13; 35mg BD = 6; 100mg QD = 10; and 75mg QD = 14. In the intermittent schedules 23 pts have been treated on D1 and 2 (2 days out of 7) per week in 2 cohorts: 170mg BD = 8; 125mg BD = 15. DLTs on the continuous schedule included rash/stomatitis (1 pt) and hyperglycemia (1 pt) at 50mg BD; fatigue (1 pt) and stomatitis (1 pt) at 100mg QD; and rash (1 pt) at 75mg QD. There were no DLTs at 170mg or 125mg BD (D1&2) on the intermittent schedule. Treatment-related toxicities (any grade) in 66 pts include: nausea (58%), fatigue (52%), diarrhea (46%), stomatitis (41%), vomiting (32%), decreased appetite (30%), maculo-papular rash (26%), and hyperglycemia (15%). PK data show that AZD2014 is rapidly absorbed (median tmax 1-1.75h). The mean single dose terminal elimination t1/2 was 3.3-5.6h and increased following multiple and/or high dosing. There was no evidence that co-administration of F had a clinically relevant impact on AZD2014 exposure. Inhibition of both mTORC1 and 2 was observed in both surrogate and tumor tissue. In the 49 pts with measureable disease, 9 confirmed (duration 1.8-22 months) and 3 unconfirmed PRs were observed. Overall, CBR (CR+PR+SD >24 weeks) was 29/66. Conclusion: Continuous and intermittent dosing of AZD2014 in combination with F is tolerable with clinical benefit observed in 44% of all pts with clinical activity observed with both schedules. Toxicities observed with the continuous dosing schedule are broadly consistent with AEs observed in other trials with mTOR inhibitors. Notably, the intermittent schedule had a different AE profile with a lower incidence of rash. AZD2014 inhibited both mTORC1 and mTORC2 in surrogate and tumor tissue and the PK data were broadly consistent with previous findings for AZD2014 single agent. A randomized phase II trial of the combination comparing both the continuous and intermittent dosing schedules is ongoing. Citation Format: Manish Patel, Erika Hamilton, Patricia M. LoRusso, W. Larry Gluck, Suzanne F. Jones, Muaiad Kittaneh, Sabina Cosulich, Elizabeth A. Harrington, Stephen Green, Wendy Burke, Donald K. Strickland, Elisabeth Oelmann, Howard A. Burris. A phase I study evaluating continuous and intermittent AZD2014 in combination with fulvestrant in patients with ER+ advanced metastatic breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT233. doi:10.1158/1538-7445.AM2015-CT233

Abstract P6-12-01: A phase I study evaluating AZD2014 in combination with fulvestrant in patients with ER+ advanced metastatic breast cancer

Background: Preclinical data suggest that patients with ER+ Breast Cancer become less sensitive to hormonal therapy by upregulation of the mTOR pathway. BOLERO-2 demonstrated that the combination of an allosteric mTOR inhibitor and an aromatase inhibitor improves progression-free survival in postmenopausal women with hormone resistant advanced breast cancer (NEJM 2012; 366:520-529). AZD2014 is a selective dual mTORC1 and mTORC2 inhibitor whilst fulvestrant is an estrogen receptor antagonist that is approved for the treatment of postmenopausal women with disease progression following antiestrogen therapy. This phase I trial assessed the safety, tolerability, pharmacokinetics, and preliminary efficacy of AZD2014 administered in combination with fulvestrant. Methods: Continuous BID or QD dosing of AZD2014 was administered in combination with fulvestrant 500 mg intramuscularly on day 1 of each 28 day cycle. An additional 500 mg dose of fulvestrant was administered on day 15 of cycle 1 as per the approved dosing schedule. Single and multiple dose AZD2014 and fulvestrant pharmacokinetic samples were obtained. Optional tumor biopsies were also obtained. Results: 43 patients (median age 61, range 32-82 years; prior chemo in the metastatic setting = 25; prior hormonal therapy = 43) have been treated in 4 dosing cohorts: 50 mg BID = 13; 35 mg BID = 6; 100 mg QD = 10; and 75 mg QD = 14. Patients have received 302+ treatment cycles (median 5 cycles/patient, range 1-21) and 4 patients continue on treatment. Review of preliminary unvalidated safety and Pk data revealed that dose-limiting toxicities included rash/mucositis (1 pt) and hyperglycemia (1 pt) at 50 mg BID; fatigue (1 pt) and mucositis (1 pt) at 100 mg QD; and rash (1 pt) at 75 mg QD. Treatment-related toxicities (any grade) include: fatigue (51%), mucositis (60%), rash (60%), nausea (47%), hyperglycemia (12%), and neutropenia (2%). Pharmacokinetic data show that AZD2014 is rapidly absorbed with a median time to maximum concentration of 1-1.75 hours and an estimated mean half-life of approximately 3.3-5.6 hours across the dose range. There is no evidence that co-administration of fulvestrant has a clinically relevant impact on exposure to AZD2014. In the 26 patients with measureable disease, 5 confirmed PRs have been observed (duration 4-18+ months) with an additional 14 patients experiencing stable disease for at least 6 months of treatment. Conclusion: Continuous QD (75mg) and BID (35 and 50 mg) administration of AZD2014 in combination with fulvestrant is tolerable with clinical benefit observed in nearly half of the patients. Toxicities observed are broadly consistent with AEs observed in other trials with antihormonal agents and other mTOR inhibitors, but seem to be well manageable. There were no new or other additive toxicities, when the two drugs were combined and AZD2014 pharmacokinetic data are broadly consistent with what has been previously observed for AZD2014 single agent. A randomized phase II trial of the combination is ongoing and an intermittent weekly dosing schedule is being explored in additional patient cohorts in the current study. Citation Format: Howard Burris III, Patricia LoRusso, W Larry Gluck, Suzanne Jones, Muaiad Kittaneh, Erika Hamilton, Stephen Green, Wendy Burke, Donald Strickland, Elisabeth Oelmann, Manish Patel. A phase I study evaluating AZD2014 in combination with fulvestrant in patients with ER+ advanced metastatic 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 P6-12-01.