Martin Zweifel

Perfusion MRI in the early clinical development of antivascular drugs: decorations or decision making tools?

IntroductionClassically, the first step in the clinical development of drugs in oncology involves assessments of dose limiting toxicity (DLT) and maximum tolerated dose (MTD). New paradigms are needed for antiangiogenic drugs and vascular disrupting agents (VDAs) as they are active at doses well below the MTD and as single agents their use might not translate into anti-tumour efficacy. MRI is able to assess the antivascular effects of antivascular drugs via changes in functional kinetic parameters; however, the usefulness of MRI in decision making has been questioned by many.ObjectivesOur aim is to review the experience of using dynamic contrast-enhanced MRI (DCE-MRI) in early clinical development of vascular directed anticancer therapies over the last decade. Thirty-nine phase I and II studies including data on more than 700 patients have been published as abstracts and/or papers, documenting DCE-MRI changes after the administration of antiangiogenic drugs and VDAs.DiscussionPerfusion MRI is helpful in assessing whether mechanistic goals are achieved, in assisting dose selection for phase II studies, in selecting subpopulations enriched for response and in predicting patient benefit. Imaging tools are increasingly available. Future challenges for imaging include correlation with clinical measures of efficacy and determining relationships with blood and serum biomarkers.

Phase I Clinical and Pharmacokinetic Evaluation of the Vascular-Disrupting Agent OXi4503 in Patients with Advanced Solid Tumors

Purpose: Preclinical studies show that OXi4503 (combretastatin A1 diphosphate, CA1P) is more potent than other clinically evaluated vascular-disrupting agents. Experimental Design: Escalating doses of OXi4503 were given intravenously over 10 minutes on days 1, 8, and 15 every 28 days to patients with advanced solid tumors. Results: Doses were escalated in single-patient cohorts from 0.06 to 1.92 mg/m2, then expanded cohorts to 15.4 mg/m2 in 43 patients. Common adverse drug reactions were hypertension, tumor pain, anemia, lymphopenia, and easily controllable nausea/vomiting and fatigue. Five patients experienced different drug-related dose-limiting toxicities, atrial fibrillation, increased troponin, blurred vision, diplopia, and tumor lysis. Prophylactic amlodipine failed to prevent adverse events. Pharmacokinetics showed dose-dependent linear increases in peak plasma concentrations and area under the curve value of OXi4503. One partial response was seen in a heavily pretreated patient with ovarian cancer. Dynamic contrast-enhanced MRI confirmed a dose effect and showed significant antivascular effects in 10 of 13 patients treated at doses of 11 mg/m2 or higher. Conclusions: The maximum tolerated dose was 8.5 mg/m2 but escalation to 14 mg/m2 was possible with only temporary reversible cerebrovascular toxicity by excluding hypertensive patients. As a tumor response was seen at 14 mg/m2 and maximum tumor perfusion reductions were seen at doses of 11 mg/m2 or higher, the recommended phase II dose is from 11 to 14 mg/m2. Clin Cancer Res; 18(5); 1415–25. ©2012 AACR.

Androgen receptor status is highly conserved during tumor progression of breast cancer

BackgroundWith the advent of new and more efficient anti-androgen drugs targeting androgen receptor (AR) in breast cancer (BC) is becoming an increasingly important area of investigation. This would potentially be most useful in triple negative BC (TNBC), where better therapies are still needed. The assessment of AR status is generally performed on the primary tumor even if the tumor has already metastasized. Very little is known regarding discrepancies of AR status during tumor progression. To determine the prevalence of AR positivity, with emphasis on TNBCs, and to investigate AR status during tumor progression, we evaluated a large series of primary BCs and matching metastases and recurrences.MethodsAR status was performed on 356 primary BCs, 135 matching metastases, and 12 recurrences using a next-generation Tissue Microarray (ngTMA). A commercially available AR antibody was used to determine AR-status by immunohistochemistry. AR positivity was defined as any nuclear staining in tumor cells ≥1 %. AR expression was correlated with pathological tumor features of the primary tumor. Additionally, the concordance rate of AR expression between the different tumor sites was determined.ResultsAR status was positive in: 87 % (307/353) of primary tumors, 86.1 % (105/122) of metastases, and in 66.7 % (8/12) of recurrences. TNBC tested positive in 11.4 %, (4/35) of BCs. A discrepant result was seen in 4.3 % (5/117) of primary BC and matching lymph node (LN) metastases. Three AR negative primary BCs were positive in the matching LN metastasis, representing 17.6 % of all negative BCs with lymph node metastases (3/17). Two AR positive primary BCs were negative in the matching LN metastasis, representing 2.0 % of all AR positive BCs with LN metastases (2/100). No discrepancies were seen between primary BC and distant metastases or recurrence (n = 17).ConclusionsMost primary (87 %) and metastasized (86.1 %) BCs are AR positive including a significant fraction of TNBCs (11.4 %). Further, AR status is highly conserved during tumor progression and a change only occurs in a small fraction (4.1 %). Our study supports the notion that targeting AR could be effective for many BC patients and that re-testing of AR status in formerly negative or mixed type BC’s is recommended.

Evaluation of cell death mechanisms induced by the vascular disrupting agent OXi4503 during a phase I clinical trial

Background:OXi4503 is a tubulin-binding vascular disrupting agent that has recently completed a Cancer Research UK-sponsored phase I trial. Preclinical studies demonstrated early drug-induced apoptosis in tumour endothelial cells at 1–3 h and secondary tumour cell necrosis between 6 and 72 h.Methods:To capture both possible outcomes of OXi4503 treatment on cell death, plasma samples for analysis by M30 and M65 ELISAs, which measure different circulating forms of cytokeratin 18 as biomarkers of apoptosis and necrosis, respectively, were collected from patients entered into the trial at early (4/6 h) and later time points (24 h, day 8 and day 15).Results:OXi4503 induced a selective dose-dependent elevation in M30 antigen levels (apoptosis) at 4/6 h and a similar elevation in M65 antigen levels at 24 h (necrosis) consistent with its preclinical cell death profile. For the purposes of investigating potential biomarker relationships to patient characteristics, the trial population was divided into three groups based on radiological and clinical response: (a) early progression, (b) progressive disease and (c) stable disease (SD)/partial response. A significant increase in antigen concentrations was measured by M65 at 24 h in the SD group compared with the two other groups (P=0.015, mean increase 30.9%).Conclusion:These results provide pharmacodynamic evidence of drug mechanism of action in cancer patients and highlight the M65 ELISA as a potentially useful biomarker assay of response to OXi4503.

Phase I trial of the androgen receptor modulator CR1447 in breast cancer patients

CR1447 (4-hydroxytestosterone, 4-OHT) binds to the androgen receptor and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells in preclinical studies. The objective of this first-in man trial was to evaluate the safety and to determine the dose of CR1447, administered as an ointment, for Phase II. Escalating doses (100, 200, 400 mg) of CR1447 were administered topically on a daily basis to patients with ER-positive/AR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. 14 patients have been treated for a total of 42 cycles. Two patients, one at dose level 100 mg and one at dose level 200 mg, showed early tumour progression and were replaced. Related adverse events were all ≤ grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose-limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447. 4-OH-androstenedione (4-OHA), a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Urine metabolites of 4-OHT and 4-OHA indicate high exposure of 4-OHT after topical administration. Oestradiol serum concentrations did not increase, confirming preclinical data that CR1447 is not converted to estrogens in vivo. In conclusion, CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day.

The Clinical Development of Tubulin Binding Vascular Disrupting Agents

Tubulin binding vascular disrupting agents (VDAs) cause a rapid change in tumour endothelial cell shape, resulting in micro-vessel blockage, loss of blood flow, and eventually tumour cell death. Spindle poisons, such as colchicine and vinblastine, disrupt tumor vasculature only at doses close to their maximum tolerated dose, which has prevented their use as VDAs. Newer agents have since been developed, which have a much wider therapeutic window, such as dolastatins and combretastatins. In this chapter, tubulin binding VDAs currently in clinical development will be discussed, with an emphasis on combretastatin A4 phosphate, which has been the first compound of this class to be discovered and to enter clinical trials.

Do Not Give Up

To the Editors: M women with advanced ovarian cancer undergo cytoreductive surgery and chemotherapy, enter a period of follow-up, and ultimately relapse. Although there are a number of therapeutic interventions in this situation with at least 7 active chemotherapy or biological agents and the possibility of secondary cytoreductive surgery, long-term survival after relapse is rare and most women succumb to their disease.1 We present a woman diagnosed with an advanced ovarian cancer who had a total of 22 relapses, 19 systemic treatments, and 6 localized palliative interventions for over a 14-year period, which, to the best of our knowledge, to more therapy than has been described before. She had no previous significant medical history but did have a positive family history of ovarian cancer; her sister died from the disease at the age of 48 years and a paternal cousin developed ovarian cancer in her 60s. On the basis of this, she elected to undergo prophylactic oophorectomies at the age of 46 years but imaging before surgery revealed an ovarian mass, which led to a pelvic clearance and omentectomy, and she was diagnosed with a stage 3 grade 3 endometrioid carcinoma of the ovary. After surgery, she had adjuvant chemotherapy in the context of the SCOTROC3 study.2 She relapsed 7 months later rendering her only partially platinum sensitive. Despite this, she went on to receive platinumcontaining chemotherapy on 10 separate occasions, and each time, this resulted in a Ca125 marker and clinical response (Fig. 1). In between and during most treatments, shewas fit and enjoyed a good quality of life. Interestingly, genetic screening on the basis of her family history and her repeated responses to platinum-based chemotherapy did not reveal a BRCA mutation when initially performed around the time of diagnosis or when repeated several years later with the assumption that improved molecular techniques would identify a mutation. It is quite possible, however, that shewill have had an as yet unidentified mutation conferring ‘‘BRCAness’’ that may have responded to Poly (ADP-ribose) polymerase inhibitors. Drugs used (Table 1) in combination with platinum in her case includeetoposide, paclitaxel, andgemcitabine. Drugs used as single agents included oral altretamine, pegylated liposomal doxorubicin, oral cyclophosphamide, and tamoxifen. Nodal relapses were treated with palliative radiotherapy to good effect and she participated in 4 different clinical trials. Her first relapse was 7 months after primary treatment and most of her subsequent treatment free intervals were between 4 and 6 months except after 2 clinical trials involving vascular disruptive agents (VDAs) where the intervals were much longer (18 months for combretastatin3 and 9 months after OXI45034). The monoclonal antibody, bevacizumab, and other antiangiogenic agents have been investigated and have a role in the treatment of ovarian cancer, but this is 1 class of drugs to which she was not exposed. The funding approval

Abstract P5-14-05: Phase 1 evaluation of the androgen receptor modulator CR1447 in patients with advanced breast cancer (SAKK 21/12)

Background: CR1447 (4-OH-testosterone, 4-OHT), a steroidal small molecule, strongly binds to the androgen receptor (AR) and has aromatase inhibiting activity. Pre-clinical studies show that CR1447 given as an ointment is efficiently absorbed and has antiproliferative activity in both ER-positive and ER-negative/AR-positive breast cancer cells. Methods: CR1447 was administered topically on a daily basis to patients with ER-positive/HER2-negative or ER-negative/PR-positive/HER2-negative advanced breast cancer pretreated with several lines of therapy. One cycle was defined as 21 days of treatment. Disease evaluation was performed at 3 and 6 months in order to determine tumor response (i.e. complete/partial remission and stable disease) in 3 cohorts of 3 evaluable patients each plus 3 confirmatory patients (dose escalation 100, 200, 400 mg). Results: 14 patients have been treated for a total of 38 cycles. Two patients are still on treatment at the time of analysis. Two patients, one in cohort 1 and one in cohort 2, showed early tumor progression and were replaced. Related adverse events were all ≤ grade 2 and included fatigue, bone and joint pain, stiffness, dry skin and mouth, nausea, sweating, urinary tract infection, rash, headache and distress. No drug-related dose limiting toxicities (DLTs) were seen. Two patients (17%) achieved stable disease at 3 months. Pharmacokinetic analysis confirmed dose-dependent transdermal uptake of CR1447, resulting in sufficient plasma concentrations of 4-OHT. 4-OH-androstenedione, a key metabolite of 4-OHT, was undetectable in most of the plasma samples. Conclusions: CR1447 administered transdermally as an ointment is well tolerated and appears to have single-agent activity in heavily pretreated ER-positive/HER2-negative and ER-negative/PR-positive/HER2-negative breast cancer patients. The recommended phase II dose is 400 mg/day. Citation Format: Schoenfeld W, Zweifel M, Thuerlimann B, Riniker S, Weder P, von Moos R, Pagani O, Bigler M, Rothgiesser KM, Pilop C, Brauchli P, Tapia C, Sessa C. Phase 1 evaluation of the androgen receptor modulator CR1447 in patients with advanced breast cancer (SAKK 21/12). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-14-05.

Abstract 5173: Androgen receptor status is highly conserved during tumor progression of breast cancer

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Introduction: Many clinical trails are ongoing targeting androgen receptor (AR) in breast cancer (BC). Anti-androgen therapy is increasingly accepted in BC patients since the new compounds have less androgenic side effects. The assessment of AR status is generally performed on the primary tumor even when treating metastatic disease. To the best of our knowledge, nothing is known regarding discrepancies of AR status between the primary tumor and the metastatic site. Therefore, we investigated AR status on a large cohort of primary BCs and matched metastases. Method: A next-generation Tissue Microarray (ngTMA) was constructed harboring 356 primary BCs, 133 matched metastases and 11 recurrences. A commercially available monoclonal AR antibody (DAKO) was used to evaluate AR-Status by immunohistochemistry. AR positivity was defined as ≥1% of nuclear staining in tumor cells. The results of the primary tumor and metastases/recurrences were compared. Additionally, the results of AR status were correlated with other pathological tumor features. Result: AR could be evaluated in 353/356 (99.2%) of primary BCs and a positivity was detected in 307 (87%). A discordant result was seen in 4.3% metastasized BCs with informative results (5/117). Three negative BCs were positive in the metastases representing 16.7% of all negative BCs with informative results (3/18). Two BCs were positive in the primary and negative in the metastases representing 2.0% of all positive BCs with metastases and informative results (2/99). No discrepancies were seen between primary and loco-regional recurrences. Further, AR expression was significantly correlated with a positive estrogen (p<0.001) and progesterone receptor (p<0.001) status and a low proliferation (≤15%) (p<0.001). Negative AR status was significantly (p<0.001) associated with a higher tumor grade. Triple negative BCs were in 11.4% AR positive (4/35). Conclusion: AR positivity is frequent in primary BCs (87%) and AR status is highly conserved during tumor progression. In a small fraction AR status changes (4.3%) either from positive to negative status or vise versa. However, even AR status is highly preserved we would recommend reevaluation of the metastatic site in negative BCs since a positive AR status can be seen in 16.7% of this subgroup. Citation Format: Andre Grogg, Katrin Pfaltz, Claudia Ladrach, Nikola Cihoric, Martin Zweifel, Coya F. M. Tapia. Androgen receptor status is highly conserved during tumor progression of 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 5173. doi:10.1158/1538-7445.AM2015-5173

Recurrent ovarian cancer: When to treat and how to assess

Recurrent ovarian cancer is rarely curable. The primary goal in “platinum-sensitive” (PS) relapse is to prolong survival, whereas palliation is often the objective in managing “platinum-resistant” (PR) disease. Whether or not to monitor patients in complete clinical remission with CA125 in order to detect recurrence should be discussed with each patient as she enters into follow-up with a review of the available literature including the strengths and limitations of the one randomized trial. Some patients will choose to be monitored with CA125 to permit optimal planning of their lives following asymptomatic recurrence, to facilitate timely secondary cytoreduction, and to provide sufficient time to evaluate conventional and novel therapy. Others will prefer not to be monitored in the absence of evidence that earlier detection prolongs survival. When CA125 is used as an endpoint in randomized clinical trials, it is important to monitor biomarker levels at similar intervals on all arms. Aside from research protocols, physicians must be aware that frequent monitoring of CA125 will reduce progression-free survival (PFS) and may result in patients being judged “platinum resistant” when they still might benefit from the drug. If CA25 is used to monitor patients during maintenance therapy with antiangiogenic agents, disease recurrence should not be based on the biomarker alone, but should be confirmed by imaging before treatment is discontinued.