Chaan Ng

Safety, Pharmacokinetics, and Efficacy of AMG 706, an Oral Multikinase Inhibitor, in Patients With Advanced Solid Tumors

PURPOSE AMG 706 is an investigational, orally bioavailable inhibitor of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and stem-cell factor receptor. This phase I, dose-finding study evaluated the safety, pharmacokinetics, and pharmacodynamics of AMG 706 in patients with refractory advanced solid tumors. PATIENTS AND METHODS AMG 706 was administered at escalating doses of 50 to 175 mg once daily or 25 mg bid for the first 21 days of a 28-day cycle. The 125-mg once-daily dose was also administered continuously. The maximum-tolerated dose (MTD), safety, pharmacokinetics, tumor response, and serum levels of proangiogenic markers were determined. RESULTS Seventy-one patients received AMG 706. The MTD was 125 mg once daily administered continuously. The most frequent adverse events were fatigue (55%), diarrhea (51%), nausea (44%), and hypertension (42%). Plasma AMG 706 concentrations increased in a dose-proportional manner with no accumulation after multiple doses. Five patients (7%) had a partial response, 35 patients (49%) had stable disease (at least through day 50), and 31 patients (44%) had progressive disease. Changes in tumor size correlated significantly with an increase in placental growth factor (P = .003) and a decrease in soluble kinase domain receptor (P = .001). CONCLUSION In this study of patients with advanced refractory solid tumors, AMG 706 was well tolerated and displayed favorable pharmacokinetics and evidence of antitumor activity. Additional studies of AMG 706 as monotherapy and in combination with various agents are ongoing.

Change in Tumor Size by RECIST Correlates Linearly With Overall Survival in Phase I Oncology Studies

PURPOSE RECIST is used to quantify tumor changes during exposure to anticancer agents. Responses are categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Clinical trials dictate a patients management options based on the category into which his or her response falls. However, the association between response and survival is not well studied in the early trial setting. PATIENTS AND METHODS To study the correlation between response as quantified by RECIST and overall survival (OS, the gold-standard survival outcome), we analyzed 570 participants of 24 phase I trials conducted between October 2004 and May 2009, of whom 468 had quantifiable changes in tumor size. Analyses of Kaplan-Meier estimates of OS by response and null Martingale residuals of Cox models were the primary outcome measures. All analyses are landmark analyses. RESULTS Kaplan-Meier analyses revealed strong associations between change in tumor size by RECIST and survival (P = 4.5 × 10(-6) to < 1 × 10(-8)). The relationship was found to be near-linear (R(2) = 0.75 to 0.92) and confirmed by the residual analyses. No clear inflection points were found to exist in the relationship between tumor size changes and survival. CONCLUSION RECIST quantification of response correlates with survival, validating RECISTs use in phase I trials. However, the lack of apparent boundary values in the relationship between change in tumor size and OS demonstrates the arbitrary nature of the CR/PR/SD/PD categories and questions emphasis placed on this categorization scheme. Describing tumor responses as a continuous variable may be more informative than reporting categoric responses when evaluating novel anticancer therapies.

Phase I Clinical Trials in 56 Patients with Thyroid Cancer: The M. D. Anderson Cancer Center Experience

INTRODUCTION Thyroid cancer is the most common endocrine malignancy. The outcomes of patients with relapsed thyroid cancer treated on early-phase clinical trials have not been systematically analyzed. PATIENTS AND METHODS We reviewed the records of consecutive patients with metastatic thyroid cancer referred to the Phase I Clinical Trials Program from March 2006 to April 2008. Best response was assessed by Response Evaluation Criteria in Solid Tumors. RESULTS Fifty-six patients were identified. The median age was 55 yr (range 35-79 yr). Of 49 patients evaluable for response, nine (18.4%) had a partial response, and 16 (32.7%) had stable disease for 6 months or longer. The median progression-free survival was 1.12 yr. With a median follow-up of 15.6 months, the 1-yr survival rate was 81%. In univariate analysis, factors predicting shorter survival were anaplastic histology (P = 0.0002) and albumin levels less than 3.5 g/dl (P = 0.05). Among 26 patients with tumor decreases, none died (median follow-up 1.3 yr), whereas 52% of patients with any tumor increase died by 1 yr (P = 0.0001). The median time to failure in our phase I clinical trials was 11.5 months vs. 4.1 months for the previous treatment (P = 0.04). CONCLUSION Patients with advanced thyroid cancer treated on phase I clinical trials had high rates of partial response and prolonged stable disease. Time to failure was significantly longer on the first phase I trial compared with the prior conventional treatment. Patients with any tumor decrease had significantly longer survival than those with any tumor increase.

A Phase I Clinical Trial of Darinaparsin in Patients with Refractory Solid Tumors

Purpose: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limiting toxicity (DLT) and maximum tolerated dose of darinaparsin in patients with advanced cancer. Experimental Design: Patients with solid malignancies refractory to conventional therapies were treated with i.v. darinaparsin daily for 5 days every 4 weeks. The starting dose (78 mg/m2) escalated to 109, 153, 214, 300, 420, and 588 mg/m2. A conventional “3 + 3” design was used. Results: Forty patients (median age, 61.5 years; median number of prior therapies, 5) received therapy; 106 cycles were given (median, 2; range, 1-12). Twenty patients reported no drug-related toxicities. No DLTs were reported at a dose of <420 mg/m2. At 588 mg/m2, two of four patients developed DLTs, including grade 3 altered mental status and ataxia. Of four patients treated at the de-escalated dose of 500 mg/m2, one developed similar toxicities. De-escalating the dose to 420 mg/m2 (n = 8) resulted in two neurologic DLTs. Further de-escalation to 300 mg/m2 (n = 3) resulted in no drug-related toxicities. Arsenic plasma levels peaked on treatment day 3, plateaued on day 5, and returned to baseline on day 7. Plasma levels varied within cohorts but increased with increasing doses. The median plasma arsenic half-life was 16.2 hours. Seven (17.5%) patients had stable disease for ≥4 months (median, 6; range, 4-11), including 4 of 17 with colorectal and 2 of 3 with renal cancer. Conclusions: The recommended dose for phase II trials is 300 mg/m2 i.v. given daily for 5 days every 4 weeks.

Exploratory Study of Hepatic Arterial Infusion Oxaliplatin With Systemic 5-Fluorouracil/ Bevacizumab in Patients With Refractory Solid Tumor and Extensive Liver Metastases

PURPOSE This pilot clinical trial explored the feasibility, safety, and efficacy of regional hepatic therapy combined with systemic anticancer agents in patients with refractory solid tumors and extensive unresectable liver involvement, including those with compromised hepatic function. PATIENTS AND METHODS Six patients with colorectal (N = 3), ovarian (N = 2), and hepatocellular carcinoma (N = 1) received intra-arterial hepatic oxaliplatin followed by intravenous 5-fluorouracil, leucovorin, and bevacizumab every 2 weeks until disease progression. All had extensive liver metastases; four had elevated baseline serum total bilirubin. Median total bilirubin was 2.8 mg/dL (range, 0.2-5.2 mg/dL). Median Child-Pugh score was 7 (range, 5-10). RESULTS Thirty treatments were delivered (2-7 per patient). Median age of patients was 57 years (range, 25-69 years). Three patients (1 with colorectal, 1 with hepatocellular, and 1 with ovarian cancer) attained partial responses. Two had failed previous oxaliplatin and cisplatin treatment. Some with elevated bilirubin at baseline had a significant drop in bilirubin with treatment (bilirubin 5.2 → 1 mg/dL, 4.8 → 1.1 mg/dL, and 5.2 → 1.8 mg/dL). The regimen was generally well tolerated; the most common side effects were grade 1 fatigue, anorexia, and/or hypertension. One patient died of enzyme-linked, immunoassay-confirmed, heparin-induced thrombocytopenia during the sixth cycle of therapy. CONCLUSION At doses tested, this regimen was safe and demonstrated antitumor activity in patients with advanced refractory malignancies involving the liver, including those with hepatic insufficiency. Further study is warranted.

Refractory Hodgkin lymphoma responds to pentostatin (2′-deoxycoformycin)

Hodgkin lymphoma in children and young adults is characterized by a high sensitivity to radiation and cytotoxic agents, resulting in cure of most, but not all, patients. The majority of young adults respond to combined-modality regimen with multi-agent chemotherapy and involved-field radiotherapy. However, there is a debate about the optimal therapeutic management in advanced stage cases of Hodgkin lymphoma because one third of these patients do not achieve a prolonged disease-free survival [1–3]. Even with high-dose chemotherapy and autologous stem cell transplantation as salvage therapy, 40 – 70% of the patients with refractory or recurrent Hodgkin lymphoma will fail to attain a durable second remission [4]. We report a 21-year old patient with heavily pretreated advanced refractory Hodgkin lymphoma who achieved a near complete metabolic response after pentostatin treatment. Pentostatin (20-deoxycoformycin) is a purine analog that inhibits adenosine deaminase. This compound is highly lymphocytotoxic and is approved by the Food and Drug Administration (FDA) for hairy cell leukemia [5]. It is also active in cutaneous and peripheral T-cell lymphomas, but there are no studies in Hodgkin lymphoma [6,7]. A 19-year-old man was diagnosed with stage IV nodular sclerosis Hodgkin lymphoma after presenting with fatigue and night sweats. After 6 cycles of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine), he achieved only partial response and relapsed in the lungs and mediastinum. Subsequently, 2 courses of ICE (ifosfamide, carboplatin and etoposide), autologous bone marrow transplantation and adjuvant radiation therapy to the relapse area in the lungs insured a brief remission for 6 months. Neither additional 2 courses of gemcitabine nor 8 courses of COPP (cyclophosphamide, vincristine, procarbazine and prednisone) provided any significant response. The patient’s low back and chest pain worsened, with weight loss and fatigue. Round-theclock opioids were needed to control the pain. He was then enrolled on a phase I/II investigational agent protocol with MDX060-01, which is a CD30 antibody, but his disease progressed. After an extensive search of the Internet, the patient self-referred himself to the University of Texas M. D. Anderson Cancer Center, to be considered for an investigational protocol with pentostatin (20-deoxycoformycin) for advanced lymphoma. An 18-FDG positron-emission tomography (fluorodeoxyglucose PET) scan revealed extensive disease, involving nodal and extra-nodal sites (Figure 1, panel A). The patient received pentostatin at 5 mg m intravenous infusions for 3 consecutive days every 3 weeks. After 2 cycles, a repeat PET scan revealed striking interval reduction in extent and degree of metabolic activity at all nodal and extra-nodal sites (Figure 1, panel B). The patient’s pain resolved and he discontinued all opioids. After an additional 2 cycles, restaging by PET (Figure 1, panel C) and CT scans (data not shown) revealed an ongoing metabolic and morphologic response (decrease of aortocaval node lymph node size from 1.7 to 1.3 cm). With the earlier course, the patient encountered significant nausea during the 3 days infusion of pentostatin, despite prophylactic ondansetron. This was subsequently controlled with systemic pre-treatment with dexamethasone 10 mg

Abstract C44: Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced cancers

Background: The mTOR inhibitors may result in upregulation of Akt, leading to undesirable cell proliferation. Metformin inhibits mTOR through different mechanisms and may enhance antitumor activity of Temsirolimus. Objectives: Primary objectives of this open-label phase 1 trial were to evaluate safety and tolerability, and to determine the maximum tolerated dose (MTD) of Temsirolimus plus Metformin combination in patients with advanced cancers refractory to standard therapies. Secondary objective was to assess clinical tumor response with this combination. Methods: A fixed dose of intravenous (IV) Temsirolimus 25mg weekly was combined with an escalating dose of oral Metformin (level-1: 500mg daily, level-2: 1000mg daily, level-3: 1500mg daily, level-4: 2000g daily) by utilizing a standard 3 + 3 design. Treatment was administered in 28-day cycles following an initial 2 weeks of Metformin titration during the first cycle. MTD was defined as the highest dose studied in which the incidence of dose-limiting toxicity (DLT) was less than 33%. Results: Twenty-one patients (male/female: 7/14) with sarcoma (n = 8), colorectal cancer (n = 3), endometrial cancer (n = 4), uterine carcinosarcoma (n = 2), ovarian cancer (n = 2) and other cancers (n = 2) were enrolled. Median age of patients was 56 (range 18-81) years. Patients had received median of 4 (range 2-11) lines of prior systemic treatments. Three DLTs were observed including one grade 3 mucositis in a patient with dose level-1, one grade 2 pneumonitis in level-2 and one grade 3 renal failure in level-4; all 3 patients who experienced DLT were able to continue treatment after dose modification. No grade 4 or 5 toxicities were observed. Patients continued treatment for a median of 11 (range 1-99; interquartile range 8-25) weeks. Conclusion: Combination of Temsirolimus and Metformin is feasible and well tolerated. We recommend a dose of Temsirolimus 25mg IV weekly and Metformin 2000mg orally daily administered in 28-day cycles for phase 2 study. The combination showed modestly promising effectiveness among this cohort of heavily pretreated patients. Further expansion is being conducted among patients with metastatic endometrial cancer. Citation Format: Muhammad Rizwan Khawaja, Vinu Madhusudanannair, Chaan Ng, Alpa Nick, Filip Janku, Sarina Piha-Paul, Robert Coleman, Pamela Soliman, Siqing Fu, David Hong, Daniel Karp, Vivek Subbiah, Apostolia Tsimberidou, Funda Meric-Bernstam, Karen Lu, Aung Naing. Phase I dose escalation study of temsirolimus in combination with metformin in patients with advanced cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C44.