Rebecca A. Moss

Phase I Dose-Escalation Study of Onartuzumab as a Single Agent and in Combination with Bevacizumab in Patients with Advanced Solid Malignancies

Purpose: This first-in-human study evaluated the safety, immunogenicity, pharmacokinetics, and antitumor activity of onartuzumab, a monovalent antibody against the receptor tyrosine kinase MET. Experimental Design: This 3+3 dose-escalation study comprised three stages: (i) phase Ia dose escalation of onartuzumab at doses of 1, 4, 10, 20, and 30 mg/kg intravenously every 3 weeks; (ii) phase Ia cohort expansion at the recommended phase II dose (RP2D) of 15 mg/kg; and (iii) phase Ib dose escalation of onartuzumab at 10 and 15 mg/kg in combination with bevacizumab (15 mg/kg intravenously every 3 weeks). Serum samples were collected for evaluation of pharmacokinetics, potential pharmacodynamic markers, and antitherapeutic antibodies. Results: Thirty-four patients with solid tumors were treated in phase Ia and 9 in phase Ib. Onartuzumab was generally well tolerated at all dose levels evaluated; the maximum tolerated dose was not reached. The most frequent drug-related adverse events included fatigue, peripheral edema, nausea, and hypoalbuminemia. In the phase Ib cohort, onartuzumab at the RP2D was combined with bevacizumab and no dose-limiting toxicities were seen. Onartuzumab showed linear pharmacokinetics in the dose range from 4 to 30 mg/kg. The half-life was approximately 8 to 12 days. There were no apparent pharmacokinetic interactions between onartuzumab and bevacizumab, and antitherapeutic antibodies did not seem to affect the safety or pharmacokinetics of onartuzumab. A patient with gastric carcinoma in the 20-mg/kg dose cohort achieved a durable complete response for nearly 2 years. Conclusions: Onartuzumab was generally well tolerated as a single agent and in combination with bevacizumab in patients with solid tumors. Clin Cancer Res; 20(6); 1666–75. ©2014 AACR.

Phase I Study of Pazopanib in Combination with Paclitaxel and Carboplatin Given Every 21 Days in Patients with Advanced Solid Tumors

Several phase III trials have shown that the addition of an antiangiogenic agent to conventional chemotherapy can improve clinical benefit in patients with advanced solid tumors. This study examined the feasibility of combining pazopanib (Votrient), an oral antiangiogenic agent, with paclitaxel and carboplatin. This 3 + 3 dose-escalation phase I study evaluated the maximum-tolerated regimen (MTR) of daily pazopanib in combination with paclitaxel 175 mg/m2 and carboplatin [dosed at area under the curve (AUC) 5 or 6] given every 21 days in patients with advanced solid tumors. Plasma samples were collected to evaluate the effect of pazopanib on the pharmacokinetics of paclitaxel and carboplatin. Thirty-four patients were enrolled. The MTR was paclitaxel 175 mg/m2 and carboplatin AUC5 with pazopanib 200 mg. The most common dose-limiting toxicities were neutropenia and thrombocytopenia. Two patients with esophageal cancer had a complete response and four patients, one each with breast, small-cell lung, pancreatic, and gastroesophageal junction cancer, had partial responses. Pazopanib at 200 mg increased paclitaxel maximal concentration (Cmax) by 43% and carboplatin (AUC5 or AUC6) Cmax by 54%. Paclitaxel and carboplatin given every 21 days at standard doses was not feasible in combination with the monotherapy pazopanib dose of 800 mg daily because of dose-limiting myelosuppression. Coadministration of pazopanib increased exposure to paclitaxel and carboplatin and likely contributed to this effect. Given the antitumor activity of this regimen, further studies are underway to determine a clinically tolerable schedule of pazopanib with paclitaxel and carboplatin. Mol Cancer Ther; 11(8); 1820–8. ©2012 AACR.

Intensity-Modulated Radiation Therapy for Rectal Carcinoma Can Reduce Treatment Breaks and Emergency Department Visits

Purpose. To compare the acute toxicities of IMRT to 3D-conformal radiation therapy (3DCRT) in the treatment of rectal cancer. Methods and Materials. Eighty-six patients with rectal cancer preoperatively treated with IMRT (n = 30) and 3DCRT (n = 56) were retrospectively reviewed. Rates of acute toxicity between IMRT and 3DCRT were compared for anorexia, dehydration, diarrhea, nausea, vomiting, weight loss, radiation dermatitis, fatigue, pain, urinary frequency, and blood counts. Fishers exact test and chi-square analysis were applied to detect statistical differences in incidences of toxicity between these two groups of patients. Results. There were fewer hospitalizations and emergency department visits in the group treated with IMRT compared with 3DCRT (P = 0.005) and no treatment breaks with IMRT compared to 20% with 3DCRT (P = 0.0002). Patients treated with IMRT had a significant reduction in grade ≥3 toxicities versus grade ≤2 toxicities (P = 0.016) when compared to 3DCRT. The incidence of grade ≥3 diarrhea was 9% among 3DCRT patients compared to 3% among IMRT patients (P = 0.31). Conclusions. IMRT for rectal cancer can reduce treatment breaks, emergency department visits, hospitalizations, and all grade ≥3 toxicities compared to 3DCRT. Further evaluation and followup is warranted to determine late toxicities and long-term results of IMRT.

A phase 1 safety study of veliparib combined with cisplatin and etoposide in extensive stage small cell lung cancer: A trial of the ECOG-ACRIN Cancer Research Group (E2511)

OBJECTIVES Veliparib (V) potentiated therapeutic efficacy of cisplatin (C) and etoposide (E) in preclinical models of SCLC. We conducted this phase 1 study to establish the safety of the combination in human subjects. MATERIALS AND METHODS The study employed the 3+3 dose escalation design to establish the safety and recommended phase 2 dose (RP2D) of V when combined with fixed doses of C (75 mg/m(2) on day 1) and E (100mg/m(2) on days 1-3) in a 21-day cycle. The starting dose of V was 60 mg (bid days 1-7) with plan to escalate to 100mg (days 1-7) or de-escalate to 40 mg (days 1-7) depending on the dose limiting toxicity (DLT) experience during cycle 1. Patients with treatment-naïve, extensive stage SCLC were included. RESULTS The study enrolled 9 patients: M/F (4/5); median age (60); White/African American (8/1). V was tolerated at the 60 mg (DLT in 0 of 3 patients) and 100mg dose (DLT in 1 of 6 patients; grade 5 cardiac failure). Veliparib at 100mg in combination with standard doses of C and E was established as the RP2D. Grades 3-5 adverse events irrespective of attribution during cycle 1 included: dehydration (1), diarrhea (1), fatigue (1), febrile neutropenia (1), heart failure (1), leukopenia (6), lymphopenia (1), nausea (2), neutropenia (8), respiratory failure (1), and thrombocytopenia (2). Investigator-assessed efficacy outcome in 7 evaluable patients were stable disease in 2/7 (28.6%), partial response in 4/7 (57.1%), and complete response in 1/7 (14.3%) patients. CONCLUSIONS This study demonstrated the safety of combining veliparib with cisplatin and etoposide in previously untreated SCLC patients.

First-in-human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors

Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade >1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 μg/mL (∼3.9–19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (>9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks. Clin Cancer Res; 23(15); 4163–9. ©2017 AACR.

Clinical Actionability of Comprehensive Genomic Profiling for Management of Rare or Refractory Cancers

To study the frequency with which targeted tumor sequencing results will lead to implemented change in care, this study assessed tumors from 100 patients for utility, feasibility, and limitations of genomic sequencing for genomically guided therapy or other clinical purpose in the setting of a multidisciplinary molecular tumor board. Comprehensive profiling led to implementable clinical action in 35% of tumors with genomic alterations.

Non-operative therapies for colorectal liver metastases

Locoregional therapies for colorectal liver metastases complement systemic therapy by providing an opportunity for local control of hepatic spread. The armamentarium for liver-directed therapy includes ablative therapies, embolization, and stereotactic body radiation therapy. At this time, prospective studies comparing these modalities are limited and decision-making relies on a multidisciplinary approach for optimal patient management. Herein, we describe multiple therapeutic non-surgical procedures and an overview of the results of these treatments.

Treatment of Multiple Endocrine Neoplasia 1/2 Tumors: Case Report and Review of the Literature

Background: Neuroendocrine tumors are uncommon tumors that are histopathologically and biologically heterogeneous and include the multiple endocrine neoplasia (MEN) 1 and 2 syndromes. The morbidity of MEN-1 and MEN-2 is often due to the symptomatology of the endocrine hormones produced, and the mortality mainly occurs from hepatic dysfunction incurred by liver metastases. At present, there is essentially no effective cure once the tumor has metastasized to the liver. Patient: We present a patient with progressive, metastatic MEN-1 with the classic ‘3 P’s’ triad of neuroendocrine tumor of the pancreas, parathyroid adenoma and a pituitary adenoma. Results: After progression on high-dose Sandostatin LAR (60 mg/month) and multiple surgeries, the patient had a partial response (40% decrease) to a novel regimen of capecitabine and temozolomide (CAPTEM) and progression-free survival of 18 months. He had minor grade 1 toxicities and no grade 2, 3 or 4 toxicities. Discussion: The history and treatment options for MEN-1/2 cancers are reviewed, as well as the data behind our novel regimen, CAPTEM. Conclusion: The CAPTEM regimen is a tolerable, safe, easy to administer oral regimen with possible efficacy for MEN-1 tumors.

Dose-Painted Intensity Modulated Radiation Therapy Improves Local Control for Locally Advanced Pancreas Cancer

Background. To evaluate the outcomes, adverse events, and therapeutic role of Dose-Painted Intensity-Modulated Radiation Therapy (DP-IMRT) for locally advanced pancreas cancer (LAPC). Methods. Patients with LAPC were treated with induction chemotherapy (n = 25) and those without metastasis (n = 20) received DP-IMRT consisting of 45 Gy to Planning Treatment Volume 1 (PTV1) including regional lymph nodes with a concomitant boost to the PTV2 (gross tumor volume + 0.5 cm) to either 50.4 Gy (n = 9) or 54 Gy (n = 11) in 25 fractions. DP-IMRT cases were compared to three-dimensional conformal radiation therapy (3D-CRT) plans to assess the potential relationship of radiation dose to adverse events. Kaplan-Meier and Cox regression analyses were used to calculate survival probabilities. The Fisher exact test and t-test were utilized to investigate potential prognostic factors of toxicity and survival. Results. Median overall and progression-free survivals were 11.6 and 5.9 months, respectively. Local control was 90%. Post-RT CA-19-9 levels following RT were predictive of survival (P = 0.02). Grade 2 and ≥grade 3 GI toxicity were 60% and 20%, respectively. In comparison to 3D-CRT, DP-IMRT plans demonstrated significantly lower V45 values of small bowel (P = 0.0002), stomach (P = 0.007), and mean liver doses (P = 0.001). Conclusions. Dose-escalated DP-IMRT offers improved local control in patients treated with induction chemotherapy for LAPC. Radiation-related morbidity appears reduced with DP-IMRT compared to 3D-CRT techniques, likely due to reduction in RT doses to organs at risk.

Long-Term Bone Marrow Suppression During Postoperative Chemotherapy in Rectal Cancer Patients After Preoperative Chemoradiation Therapy

PURPOSE/OBJECTIVE(S) To quantify ensuing bone marrow (BM) suppression during postoperative chemotherapy resulting from preoperative chemoradiation (CRT) therapy for rectal cancer. METHODS AND MATERIALS We retrospectively evaluated 35 patients treated with preoperative CRT followed by postoperative 5-Fluorouracil and oxaliplatin (OxF) chemotherapy for locally advanced rectal cancer. The pelvic bone marrow (PBM) was divided into ilium (IBM), lower pelvis (LPBM), and lumbosacrum (LSBM). Dose volume histograms (DVH) measured the mean doses and percentage of BM volume receiving between 5-40 Gy (i.e.: PBM-V5, LPBM-V5). The Wilcoxon signed rank tests evaluated the differences in absolute hematologic nadirs during neoadjuvant vs. adjuvant treatment. Logistic regressions evaluated the association between dosimetric parameters and ≥ grade 3 hematologic toxicity (HT3) and hematologic event (HE) defined as ≥ grade 2 HT and a dose reduction in OxF. Receiver Operator Characteristic (ROC) curves were constructed to determine optimal threshold values leading to HT3. RESULTS During OxF chemotherapy, 40.0% (n=14) and 48% (n=17) of rectal cancer patients experienced HT3 and HE, respectively. On multivariable logistic regression, increasing pelvic mean dose (PMD) and lower pelvis mean dose (LPMD) along with increasing PBM-V (25-40), LPBM-V25, and LPBM-V40 were significantly associated with HT3 and/or HE during postoperative chemotherapy. Exceeding ≥36.6 Gy to the PMD and ≥32.6 Gy to the LPMD strongly correlated with causing HT3 during postoperative chemotherapy. CONCLUSIONS Neoadjuvant RT for rectal cancer has lasting effects on the pelvic BM, which are demonstrable during adjuvant OxF. Sparing of the BM during preoperative CRT can aid in reducing significant hematologic adverse events and aid in tolerance of postoperative chemotherapy.