Tag Archives: paclitaxel

Synergistic Anti-Tumor Effect of CRM197 & Paclitaxel in Ovarian Cancer

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CRM197, an inhibitor of heparin-binding EGF-like growth factor (HB-EGF), produces a synergistic ovarian cancer anti-tumor effect when combined with paclitaxel, according to study results published in the March 15th issue of the International Journal of Cancer.  The investigators, Dr. Shingo Miyamoto and his colleagues, are affiliated with the Fukuoka University in Japan.  “The treatment of CRM197 in conjunction with paclitaxel results in a marked synergistic anti-tumor effect in ovarian cancer cells in vivo, suggesting a novel combination therapy for ovarian cancer patients including those showing chemo-resistance.”  Accordingly, the investigators generally concluded that inhibitory agents against HB-EGF, such as CRM197, represent possible chemotherapeutic and chemosensitizing agents for ovarian cancer. …

CRM197, an inhibitor of heparin-binding EGF-like growth factor (HB-EGF), produces a synergistic ovarian cancer anti-tumor effect when combined with paclitaxel, according to study results published in the March 15th issue of the International Journal of Cancer.  The investigators, Dr. Shingo Miyamoto and his colleagues, are affilitated with the Fukuoka University in Japan.

According to the researchers, HB-EGF plays a pivotal role in tumor growth and clinical outcomes in patients with ovarian cancer, thereby making it a target for future ovarian cancer therapy. CRM197 is a non-toxic variant of the diphtheria toxin.  The investigators conducted studies in which CRM197 and paclitaxel (Taxol®) were tested against ovarian cancer cell cultures (in vitro) and overexpressing HB-EGF ovarian cancer cells which were injected into mice.

The investigators discovered that paclitaxel induced transient ERK activation and sustained activation of JNK and p38 MAPK, effects that were reduced by overexpression of HB-EGF. CRM197 effectively suppressed the paclitaxel-induced anti-apoptotic signals mediated by ERK and Akt and enhanced the pro-apoptotic signals JNK and p38 MAPK.

The investigators also noted that in the mice with ovarian cancer xenografts, paclitaxel and CRM197 completely blocked tumor formation at doses of 10 mg/kg paclitaxel and 5 mg/kg CRM197.

Based on the foregoing, Miyamoto et. al. concluded that “the enhancement of HB-EGF expression abrogates the antitumor effect of paclitaxel by altering the balance of anti-apoptotic and pro-apoptotic signals induced by paclitaxel. The treatment of CRM197 in conjunction with paclitaxel results in a marked synergistic anti-tumor effect in ovarian cancer cells in vivo, suggesting a novel combination therapy for ovarian cancer patients including those showing chemo-resistance.”  Accordingly, the investigators generally concluded that inhibitory agents against HB-EGF, such as CRM197, represent possible chemotherapeutic and chemosensitizing agents for ovarian cancer.

“Phase 1 [clinical] study of the use of CRM197 has already started at Fukuoka University for patients with advanced ovarian cancer under the approval of the ethical committee,” the investigators added.

Primary Sources:

Evaluation of Neoadjuvant Chemotherapy and Debulking Followed by Intraperitoneal Chemotherapy in Women with Stage III and IV Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer

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It is well known that intraperitoneal (IP) chemotherapy prolongs survival in optimally cytoreduced (or debulked) ovarian cancer patients.  For patients who can not be optimally debulked, it is possible to administer neoadjuvant chemotherapy to place that patient in a position to be optimally debulked (i.e., 1 cm or less of residual disease post surgery) , thereby allowing the use of post-surgery IP chemotherapy (assuming optimal cytoreduction is achieved through surgery). This theory was tested in a Phase II clinical study (S0009) conducted by the Southwest Oncology Group (SOG). …

It is well known that intraperitoneal (IP) chemotherapy prolongs survival in optimally cytoreduced (or debulked) ovarian cancer patients.  For patients who can not be optimally debulked, it is possible to administer neoadjuvant chemotherapy to place that patient in a position to be optimally debulked (i.e., 1 cm or less of residual disease post surgery) , thereby allowing the use of post-surgery IP chemotherapy (assuming optimal cytoreduction is achieved through surgery). This theory was tested in a Phase II clinical study (S0009) conducted by the Southwest Oncology Group (SOG).

In SOG Study S009, researchers sought to evaluate overall survival (OS), progression-free survival (PFS), percentage of patients optimally debulked, and toxicity in Stage III/IV ovarian cancer patients treated with this strategy.

As part of the study, women with stage III/IV (pleural effusions only in stage IV) epithelial ovarian cancer, and fallopian tube or primary peritoneal carcinoma that presented with bulky disease were treated with neoadjuvant intravenous (IV) paclitaxel and carboplatin.  If, after neoadjuvant IV chemotherapy, the patient experienced a 50% or greater decrease in her CA125 tumor marker, cytoreduction surgery was performed.  If optimal debulking was achieved, the patient received IV paclitaxel, IP carboplatin and IP paclitaxel post-surgery.

The results of the study are set forth below.

  • 62 patients were registered for the study, of which four were ineligible.
  • 56 patients were evaluated for neoadjuvant chemotherapy toxicities. One patient died of pneumonia. Five patients had grade 4 toxicity, including neutropenia, anemia, leukopenia, anorexia, fatigue, muscle weakness, respiratory infection, and cardiac ischemia.
  • 36 patients received debulking surgery, and two patients had grade 4 hemorrhage.
  • 26 patients received post-cytoreduction chemotherapy. Four had grade 4 neutropenia.
  • At a median follow-up of 21 months, median PFS is 21 months and median OS is 32 months for all 58 patients.
  • PFS and OS for the 26 patients who received IV/IP chemotherapy is 29 and 34 months, respectively

The researchers performing the study concluded that the results compare favorably with other studies of sub-optimally debulked (i.e., >1 cm of residual disease post surgery) patients.

Primary Source:  Phase II evaluation of neoadjuvant chemotherapy and debulking followed by intraperitoneal chemotherapy in women with stage III and IV epithelial ovarian, fallopian tube or primary peritoneal cancer: Southwest Oncology Group Study S0009; Tiersten AD, Liu PY, Smith HO et. al., Gynecol Oncol. 2009 Mar;112(3):444-9. Epub 2009 Jan 12.

Sometimes More Is Less: Evaluation of Experimental Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer; A Phase III Trial of the Gynecologic Cancer InterGroup

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“… Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent [gemcitibine, liposomal doxorubicin or topotecan] provided no benefit in PFS [progression-free survival] or OS [overall survival] after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.”

“Michael A. Bookman,* Mark F. Brady, William P. McGuire, Peter G. Harper, David S. Alberts, Michael Friedlander, Nicoletta Colombo, Jeffrey M. Fowler, Peter A. Argenta, Koen De Geest, David G. Mutch, Robert A. Burger, Ann Marie Swart, Edward L. Trimble, Chrisann Accario-Winslow, and Lawrence M. Roth

From the Fox Chase Cancer Center, Philadelphia, PA; Gynecologic Oncology Group Statistical and Data Center, Buffalo, NY; Franklin Square Hospital; Baltimore, MD; Guy’s Hospital, London, United Kingdom; Arizona Cancer Center, Tucson, AZ; Australia New Zealand Gynaecological Oncology Group, Camperdown, Australia; European Institute of Cancer Research, Milano, Italy; Ohio State University, Columbus, OH; University of Minnesota School of Medicine, Minneapolis, MN; University of Iowa Hospitals and Clinics, Iowa City, IA; Washington University School of Medicine, St. Louis, MO; University of California, Irvine Medical Center, Orange, CA; University College London and Medical Research Council Clinical Trials Unit, London, United Kingdom; National Cancer Institute, Bethesda, MD; and Indiana University School of Medicine, Indianapolis, IN.

* To whom correspondence should be addressed. E-mail: michael.bookman@fccc.edu

Purpose: To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel.

Patients and Methods: Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons.

Results: Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup.

Conclusion: Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.”

Quoted Source:  Evaluation of New Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer: A Phase III Trial of the Gynecologic Cancer InterGroup; Bookman MA et. al., J Clin Oncol. 2009 Feb 17. [Epub ahead of print].

2008 ASCO Annual Meeting Abtracts Highlight Several Drugs That Show Promise Against Drug Resistant Ovarian Cancer

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There were several drugs highlighted in clinical trial abstracts presented at the 2008 American Society of Clinical Oncology (ASCO) Annual Meeting that demonstrated varying degrees of effectiveness against drug resistant (i.e., recurrence within 6 to 12 months after completion of first line treatment) and/or drug refractory (i.e., recurrence within 6 months after completion of first line treatment) ovarian cancer. By “effectiveness,” we mean generally that the drug or drug combination produced a complete response, partial response, and/or disease stabilization (and in a few cases, a significant drop in the CA-125 tumor marker) in ovarian cancer tumors. To better understand how to intrepret a medical study abstract, click here. The 2008 ASCO Annual Meeting was held in Chicago, Illinois on May 30 – June 3, 2008.

A list of the drugs/drug combinations is provided below. Any drug covered in depth through an earlier H*O*P*E*™ weblog post is noted. We also included 2008 ASCO Annual Meeting abstracts that provide “solid tumor” clinical trial results with respect to studies that enrolled patients with ovarian cancer tumors. When evaluating the potential enrollment in a clinical trial at various treatment points, an ovarian cancer survivor should evaluate trials dedicated to ovarian cancer patients in entirety, as well as general “solid tumor” trials that allow enrollment of ovarian cancer patients. Generally, a patient should give first priority to dedicated ovarian cancer trials and use the solid tumor trials as a “backup” to the ovarian cancer trials. All questions regarding the priority assigned to, or proper sequencing of, clinical trials should be discussed in detail with your doctor(s). Treatment priority and sequencing issues arise, for example, when enrollment in one clinical trial potentially disqualifies the patient for a subsequent second clinical trial based upon the protocol (i.e., inclusion/exclusion criteria) of the second trial. This example assumes that both clinical trials are currently enrolling patients when trial enrollment is being evaluated by you and your doctor.

Abbreviation Legend:

ABSTR=2008 American Society of Clinical Oncology Annual Meeting Abtract; ASCO=American Society of Clinical Oncology; CA-125=cancer antigen 125; CEA=Carcinoembryonic Antigen (Tumor Marker); CR=Complete Response; CT=Computed Tomography

CTC=Common Toxicity Criteria; DCE-MRI=Dynamic Contrast Enhanced Magnetic Resonance Imaging; DLT=Dose Limiting Toxicity; DP=Disease Progression; EOC=Epithelial Ovarian Cancer; G=Grade of Adverse Drug Effect;

GCIG=Gynecologic Cancer Intergroup; GOG–Gynecologic Oncology Group; MTD=Maximum Tolerable Dose; mg/m²=milligrams per metre squared; NCI=National Cancer Institute; OR=Objective Response; OS=Overall Survival;

PET=Positron Emission Tomography Scanning; PK=Pharmacokinetics; PO=Oral Administration; PR=Partial Response; PFS=Progression Free Survival; RECIST=Response Evaluation Criteria in Solid Tumors; RR=Response Rate; SD=Stable Disease

SNS-595 (Voreloxin®):

NOV-002 & Carboplatin (Paraplatin®):

  • NOV-002 plus carboplatin in platinum-resistant ovarian cancer (2008 ASCO Abstract #5593). Patients were heavily pretreated with 11/15 patients having received 3 prior [treatment] lines. Toxicity was mild-moderate with no G4 toxicity. There was no febrile neutropenia. The most common toxicities were nausea and fatigue, as well as abdominal pain and bowel obstruction thought to be related to underlying disease. To date, there is 1 patient with PR, 7 patients with SD and 5 patients with PD, with 1 patient off-trial for patient discretion. PFS is 14 weeks. Patients tolerated this regimen extremely well, with most toxicity attributable to carboplatin alone. Conclusion: The PFS was longer than expected, with a significant proportion of these platinum resistant patients achieving clinical benefit with prolonged stable disease. [61% disease control (CR+PR+SD) rate]

Picoplatin & Pegylated Liposomal Doxorubicin (Doxil®):

  • Final results of a phase I study of picoplatin and pegylated liposomal doxorubicin [e.g. Doxil™] in advanced solid tumor malignancies (2008 ASCO Annual Mtg. Abstr. #2568 ): Picoplatin is a novel, sterically hindered platinum(II) complex designed to circumvent mechanisms of platinum resistance. Given the single agent activity seen in multiple tumor types, we conducted a phase I study of picoplatin in combination with pegylated liposomal doxorubicin (PLD) in patients with advanced solid tumors. The Phase 1 trial enrolled 16 patients with advanced solid tumors who had received up to three prior regimens for metastatic disease. Patients were administered picoplatin followed by liposomal doxorubicin on day one of a 28-day cycle. Four dose levels of picoplatin and pegylated liposomal doxorubicin were tested: 100/20, 100/30, 100/40 and 120/40 (all mg/m2). A total of 62 courses of treatment were delivered to 16 patients with a median number of four cycles per patient. A total of 12 patients were evaluable for response. One patient experienced a CR (primary peritoneal cancer) and four experienced a PR (including three of five patients with ovarian cancer). Hematologic and non-hematologic toxicity were mild. Conclusion: This study suggests that picoplatin and liposomal doxorubicin is an active combination with promising results and can be given at standard dose levels with a minimal increase in toxicity. [41% disease control (CR+PR+SD) rate among evaluable patients]

Weekly Topotecan (Hycamtin™) Monotherapy:

  • Phase II study of weekly topotecan in recurrent ovarian cancer: duration of response based on a prolonged follow-up (ASCO Annual Mtg. Abstr. #16549). Nineteen patients (median age 52 yrs, range 45-72) with EOC who progressed after 3 (11/19 patients = 57.9%), 4 (7/19 patients= 36.8%) or 5 (1/19 patients= 5.3%) previous lines of chemotherapy were treated with Topotecan at the dose of 2.0 mg/m2 via a 30-minute intravenous infusion once every week until disease progression, unacceptable toxicity or when a stability of disease was reached. Results: All patients were evaluable for toxicity and clinical response. 16/19 patients enrolled (84.2%) had stage III-IV disease. Median number of chemotherapy cycles was 7 (range 3 – 12). A total of 107 cycles were administered. Dose reduction was necessary for 13% of the cycles. Main toxicities included anemia (G1-G2=57.9%), leucopenia (G1-G2=15.8%), thrombocytopenia (G1-G2=10.5%) and asthenia (20%). No one showed a CR, while 5/19 patients experienced a PR (26.4%), 6/19 patients experienced SD (31.5%), and 8/19 patients (42.1%) experienced DP. The median PFS was 12 weeks in patients with PR; SD was maintained for a median time of 14 weeks. Conclusion: The rate of patients with ongoing stable disease (31.5%) suggests that the clinical benefit of weekly topotecan may be expected also in patients with no other viable therapeutic options. [57% disease control (CR+PR+SD) rate among evaluable patients]

Azacitidine & Carboplatin:

Combretastatin A4 Phosphate (Zybrestat™) and Bevacizumab (Avastin™):

BSI-201:

Belinostat (PXD101):

SU11248/Sunitinib (Sutent®):

AZD2281 (KU-0059436):

  • AZD2281, a PARP (poly ADP-ribose polymerase) inhibitor with single agent anticancer activity in patients with BRCA deficient ovarian cancer: Results from a phase I study (2008 ASCO Annual Mtg. Abstr. #5510) Thirty-two patients with BRCA-deficient ovarian cancer (i.e., patients with BRCA gene mutations) the majority of whom were platinum resistant/refractory are so far evaluable for response. All evaluable patients had either received treatment for at least 8 weeks (2 cycles) or progressed prior to completion of 2 cycles. Fourteen patients have achieved PR, 13 patients meeting GCIG- CA125 criteria and 10 patients meeting RECIST criteria. Of the responders, 1 patient has been on drug > 56 weeks whilst 7 patients have maintained responses for > 24 weeks. SD was seen in an additional 8 patients, 7 of whom continue on drug and 3 patients had SD > 16 weeks. Responses were seen at all dose levels from 100mg bd and above. Conclusion: AZD2281 is well tolerated and has demonstrated compelling activity in patients with BRCA deficient ovarian cancer. Responses were seen in all patient groups including platinum resistant disease. Updated efficacy data, together with a correlation of potential predictive factors including platinum free interval will be presented on a total planned cohort of 46 patients with BRCA-deficient ovarian cancer. A randomised study in BRCA-deficient ovarian cancer has been planned. [68% disease control (CR+PR+SD) rate among evaluable patients]

Gemcitibine (Gemzar™) & Epirubicin (Ellence™):

Belinostat/PXD101, Carboplatin (Paraplatin®) & Paclitaxel (Taxol™):

Pegylated Liposomal Doxorubicin (Doxil®) & Gemcitabine (Gemzar®):

Pemetrexed/LY231514 (Altima®):

Sorafenib (Nexavar™):

  • Phase II trial of sorafenib in persistent or recurrent epithelial ovarian cancer (EOC) or primary peritoneal cancer (PPC): A Gynecologic Oncology Group (GOG) study (2008 ASCO Annual Mtg. Abstr. #5537). Sorafenib is a tyrosine kinase inhibitor targeting raf and other receptor kinases (VEGF-R, PDGF-R, Flt3, c-KIT). Sorafenib may have anti-angiogenic activity through inhibition of VEGF-R. This phase II study was conducted to assess the activity and tolerability of sorafenib in patients with recurrent EOC. Methods: This was an open label multi-institutional phase II study …. Eligible patients had persistent or recurrent EOC/PPC after 1-2 prior cytotoxic regimens, measurable or detectable (e.g. by CA125) disease, and GOG performance status < 2. Patients were required to have progressed within 12 months of completing platinum based therapy. Treatment consisted of sorafenib 400 mg orally bid until disease progression or prohibitive toxicity. Primary endpoints were PFS at 6 months and toxicity by NCI criteria. Secondary endpoints were tumor response and duration of PFS/OS. Results: 73 patients were enrolled from 10/04 to 5/07 and as of 12/2007, 68 patients are evaluable (2 ineligible and 3 too early) for toxicity. Median age was 60 (range 33-80) years and prior treatment consisted of 1 regimen in 40 patients and 2 regimens in 28 patients. Significant G3 and G4 toxicities included: rash (12 patients), metabolic (10 patients), gastrointestinal (3 patients), cardiovascular (2 patients), and pulmonary (2 patients). No treatment related deaths were recorded. Only patients with measurable disease were used to assess efficacy. Among the 59 patients with measurable disease, 12 survived PFS at least 6 months. Three patients are yet to be determined. Two patients had PR; 20 had SD; 30 had DP, and 7 could not have their tumor assessed. Conclusions: Preliminary results suggest that sorafenib is tolerated in patients with recurrent EOC with dermatologic and metabolic abnormalities being the most common toxicities. Efficacy data is expected to reach maturity and be analyzed in the spring of 2007, and comprehensive results will be presented. [42% disease control (CR+PR+SD) rate among evaluable patients]

Topotecan (Hycamtin™) & Bevacizumab (Avastin™):

  • Phase II prospective study of weekly topotecan and bevacizumab in platinum refractory ovarian cancer or peritoneal cancer (OC) (2008 ASCO Annual Mtg. Abstr. #5551). Patients (pts) with platinum refractory OC have limited treatment options. Bevacizumab, an anti-angiogenesis agent has demonstrated efficacy in recurrent ovarian cancer. Bevacizumab combined with chemotherapy in other solid tumors has improved efficacy compared with bevacizumab or chemotherapy alone. Topotecan, an active drug in recurrent OC has been used in a weekly fashion with less toxicity and more acceptability than a standard 5 day regimen. Topotecan and bevacizumab have non-overlapping toxicities. We studied the efficacy and tolerability of weekly topotecan and bevacizumab in patients with platinum refractory OC. Methods: The primary objectives of this study were to evaluate PFS, OS, OR rate and toxicity of this combination regimen. Eligible pts included those with platinum refractory OC (recurrence < 6 months of platinum therapy) who had received a maximum of 2 prior chemotherapy regimens. Results: Twenty-two pts have been enrolled to date, with 11 pts remaining on study and 18 now evaluable. Best responses for the 18 evaluable pts were: 22.2% PR (n=4), 27.8% SD (n=5), and 50% DP (n=9). Eleven pts went off study due to DP (based on CT scan RECIST criteria [n=6] or general deterioration and/or bowel obstruction [n=5]). Median duration on study for the 18 evaluable pts was 15 wks (range 5-63 weeks). Four pts have had PFS >5 months. The 18 evaluable pts received a total of 91 treatment cycles. No pt went off study due to treatment related toxicity or suffered a bowel perforation. Conclusions: Combination bevacizumab and topotecan administered in a weekly fashion demonstrate good activity in platinum refractory OC with acceptable toxicity. G3-G4 Hematologic or Hypertensive Toxicities. [50% disease control (CR+PR+SD) rate among evaluable patients]

Lapatinib (Tykerb™), Carboplatin (Paraplatin®) & Paclitaxel (Taxol™):

  • Phase I/II lapatinib plus carboplatin and paclitaxel in stage III or IV relapsed ovarian cancer patients (2008 ASCO Annual Mtg. Abstr. #5556). The purpose of this study was to establish the MTD and evaluate DLTs and response to therapy of combination therapy with carboplatin/paclitaxel and lapatinib, an oral dual tyrosine kinase inhibitor of both ErbB1 and ErbB2, in Stage III /IV relapsed ovarian cancer. Methods: This was an open-label, multicenter, phase I/II study of carboplatin/paclitaxel in combination with single agent lapatinib in Stage III/IV relapsed ovarian cancer patients. Measurable disease, adequate organ function and ECOG performance status of 0-2 were required. Results: 25 ovarian cancer patients are enrolled and four are too early to be evaluable. The median age is 57 (range 39-81). The median number of prior therapeutic regimens is 4 (range 1-10). GI toxicities were primarily < grade 2 and were successfully treated with aggressive bowel management. 10 patients (pts) experienced G3 toxicities. 4 pts- leukopenia, 2 pts-neutropenia, 2 pts-hyperglycemia, 2 pts-allergic reactions to carboplatin, 1 pt-thrombocytopenia, 1 pt-lymphopenia, 1 pt-hypokalemia, 1 pt-nausea, 1 pt-diarrhea, 1 pt-bowel obstruction. Response to therapy to date is: CR=21%, PR=29%, SD=29%, PD=21%. Two patients who were in complete remission both stopped IV chemotherapy and were maintained only with lapatinib. One is still in remission after six months and one relapsed. Conclusions: Lapatinib, an oral targeted molecular therapy which inhibits both EGFR 1 and 2 tyrosine kinase activity, can be safely administered with a weekly regimen of carboplatin and paclitaxel in heavily pretreated, ovarian cancer patients. The high response rates seen warrant further investigation. [79% disease control (CR+PR+SD) rate among evaluable patients]

Ifomide, Epirubicin, & Cisplatin:

NKTR-102 (Pegylated irinotecan):

  • Phase I dose finding and pharmacokinetic study of NKTR-102 (PEGylated irinotecan): Early evidence of anti-tumor activity (2008 ASCO Annual Mtg. Abstr. #13518 ). NKTR-102 is a novel pegylated form of irinotecan with superior efficacy against a range of xenografts compared with irinotecan. Sustained tumor inhibition is associated with increased SN38 exposure. A phase I trial of NKTR-102 was conducted to establish the MTD and to characterize safety and PK in patients (pts) with refractory solid tumors. No CTC Grade 4 toxicity was observed. G3 diarrhea was dose limiting. Other toxicities included transient uncomplicated G3 neutropenia and transient infusion related visual disturbance. PK data are available for 12 pts. Two partial responses were observed in pts with advanced cervical cancer and small cell lung cancer. Anti-tumor activity was seen in 4 other pts; ovarian: CA-125 decreased from 2557 to 518, Hodgkin’s disease: 28% radiologic improvement with symptomatic benefit, adrenocortical: cortisol levels normalized, metabolic response by PET, esophageal: CEA decreased from 35.5 to 13.6, metabolic response by PET. Conclusions: NKTR-102 shows early evidence of activity in a wide spectrum of tumors. Cumulative SN38 exposure is 1.2 to 6.5 fold higher than that predicted for irinotecan. Toxicity is manageable; diarrhea (not neutropenia) is dose limiting.

ON 01910.Na:

  • Phase I study of ON 01910.Na, a novel polo-like kinase 1 pathway modulator, administered as a weekly 24-hour continuous infusion in patients with advanced cancer (2008 ASCO Annual Mtg. Abstr. #2515). ON 01910.Na induces G2/M cell cycle arrest, apoptosis, and cell death in a broad spectrum of cancer cells, but not in non-neoplastic cells. In vitro, cell killing is dependent on drug exposure time. Based on these preclinical findings, a weekly 24hr continuous infusion (CI) study to determine safety and MTD of ON 01910.Na was initiated. Methods: Patients with advanced cancers received ON 01910.Na as a weekly 24hr CI. Twenty-three pts (7:16 M:F, 45-80 yrs) have received ON 01910.Na. G2 toxicities (2-grade increase over baseline) included fatigue (3 pts) and anorexia (1 pt). Fatigue (11/23 pts) was the most common side effect, with no G3 or greater fatigue observed. Overall, three G3 events occurred, none of which were drug-related. The best response was a pt with advanced ovarian cancer who maintained stable disease for 36 wks of treatment. Conclusions: ON 01910.Na is well tolerated as a weekly 24h continuous infusion. In the dose range studied, the drug exhibited non-linear kinetics with rapid attainment of plasma concentrations that are cytotoxic to cancer cells in vitro, but have limited end-organ toxicity in vivo. Study data continues to accrue, and we expect to recommend a phase II dose shortly. Further analysis and combination phase I studies are planned.

BAY 73-4506:

  • Phase I study of BAY 73-4506, an inhibitor of oncogenic and angiogenic kinases, in patients with advanced solid tumors: Final results of a dose-escalation study (2008 ASCO Annual Mtg. Abstr. #2558 ). BAY 73-4506 is a potent tyrosine kinase inhibitor of receptor tyrosine kinases (VEGFR, PDGF, RET, KIT, FGFR) and serine/threonine kinases (raf and p38MAPK). In tumor xenograft models, BAY 73-4506 demonstrated a broad spectrum antitumor activity. Methods: This phase I study was a dose-escalation trial investigating the safety, PK, and pharmacodynamic (PD) profile of BAY 73-4506, given orally in 21 days on/7 days off cycles, until discontinuation due to toxicity or tumor progression. PK was assessed on days 1 and 21 of cycle 1. PD markers including DCE-MRI, soluble VEGFR-2 (sVEGFR-2) and VEGF plasma levels were assessed at each cycle. Tumor response was evaluated as per RECIST. Results: 52 patients (pts) with solid tumors and progressive disease were enrolled and treated with doses of 10 to 220 mg once daily. Frequent tumor types included colorectal cancer (CRC) (31%), malignant melanoma (10%), and ovarian cancer (10%). The median treatment duration was 49.5 days (min. 3, max. 609). Drug-related adverse events (AEs) of all grades reported in >20% of pts were hoarseness (54%), dermatological toxicities (50%; CTC G3-G4: 13%), mucositis (35%), diarrhea (25%; CTC 3: 2%), fatigue (23%; CTC 3: 2%), and hypertension (23%; CTC 3: 6%). Treatment-related AEs leading to dose reduction, interruption or discontinuation were hand foot skin reaction (15%), diarrhea (8%), and thrombopenia (6%). Of the 33 evaluable pts, 9% achieved a partial response (PR), 64% had stable disease (SD), at least 7 weeks after start of treatment, and 48% had SD or PR for more than 11 weeks. Conclusions: The recommended phase II dose for BAY 73-4506 is 160 mg daily, using the 21 days on/7 days off treatment schedule. Clinical activity (PR+SD) has been demonstrated in 73% of the evaluable pts. An extension cohort (dose level 160 mg) has been started.

Selenium Added to Carboplatin & Paclitaxel Generates Significant Synergy in 40% of Ovarian Cancer Patients Tested

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According to lead author Lorna Rodriguez, M.D., PhD [appearing in the right side photo], chief of gynecologic oncology at [The Cancer Institute of New Jersey] CINJ and associate professor of obstetrics, gynecology and reproductive sciences at UMDNJ-Robert Wood Johnson Medical School, the study of 30 patients so far shows that selenium can be safely given in combination with carboplatin and paclitaxel. Furthermore, she notes, selenium may help treatment efficacy as indicated by four patients having complete disappearance of disease, and eight patients having their tumors decrease in size by more than 30 percent.

“New research findings from a top clinical investigator at The Cancer Institute of New Jersey (CINJ) indicate the potential for more targeted treatment of ovarian cancer, which is expected to claim more than 15,000 lives nationwide this year, with 480 in New Jersey. The study, to be presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago later this month, looks at the effects of a mineral called selenium in combination with the standard treatment for the disease. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.Lorna Rodriguez, M.D., Ph.D.

Currently, the standard of care involves the drugs carboplatin and paclitaxel, which have shown the ability to shrink ovarian cancer tumors; however, that shrinkage may not last for a long period due to the development of drug resistance. Previous data shows that selenium inhibits the development of a tumor’s resistance to carboplatin. The current study couples selenium with the two drugs with the goal of preventing or slowing drug resistance.

According to lead author Lorna Rodriguez, M.D., PhD [appearing in the right side photo], chief of gynecologic oncology at CINJ and associate professor of obstetrics, gynecology and reproductive sciences at UMDNJ-Robert Wood Johnson Medical School, the study of 30 patients so far shows that selenium can be safely given in combination with carboplatin and paclitaxel. Furthermore, she notes, selenium may help treatment efficacy as indicated by four patients having complete disappearance of disease, and eight patients having their tumors decrease in size by more than 30 percent. The results show that a serum marker [i.e., CD44] may predict which women will benefit from selenium therapy.

Dr. Rodriguez notes the findings could finally lead to more tailored treatment, ‘Because symptoms of ovarian cancer are often silent, many patients who are diagnosed with the disease are usually in an advanced stage. Having such a targeted treatment available to these patients could very well mean a longer survival outcome and increased quality of life.’

The CINJ team – which includes gynecologic oncologists Darlene Gibbon, M.D.; Mira Hellmann, M.D.; Wilberto Nieves-Neira, M.D.; and Ami Vaidya, M.D.; Director of Pharmacy, Susan Goodin, PharmD, FCCP, BCOP; pharmacologist Murugesan Gounder, Ph.D.; and research teaching specialist Neelakandan Muthukumaran – is planning Phase II studies for patients with ovarian and endometrial cancers in the future.

Rodriguez will be among the more than 30,000 cancer specialists from around the globe, who will showcase advances in clinical research at the annual ASCO meeting.

About The Cancer Institute of New Jersey
The Cancer Institute of New Jersey is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center, and is dedicated to improving the prevention, detection, treatment and care of patients with cancer. CINJ’s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice quite literally bringing research to life. The Cancer Institute of New Jersey is a center of excellence of UMDNJ-Robert Wood Johnson Medical School. To support CINJ, please call the Cancer Institute of New Jersey Foundation at 1-888-333-CINJ.”

[Quoted Source: New Treatment Implications for Ovarian Cancer Unveiled, NewsWire Medical News Release dated May 16, 2008].

Comment: This study shows promise for the use of selenium, carboplatin (Paraplatin®) and paclitaxel (Taxol®) as a potential “revised” standard of care, albeit only a small study. If the serum marker CD44 can ultimately identify those patients that will respond to this combination at the earliest point in treatment, this triple agent combination can be used as a “targeted” or “personalized” therapy. It is important to note that the selenium used in this study was administered intravenously at various dosages and was not administered as an oral vitamin supplement.

Additional Information:

Epirubicin Improves Overall Survival Better Than Ifosfamide When Combined with Paclitaxel and Cisplatin

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Epirubicin (Ellence®) produced longer median overall survival (OS) than ifosfamide (Ifex®) in a recent phase II randomized clinical trial comparing (i) cisplatin, paclitaxel and ifosfamide, with (ii) cisplatin, paclitaxel and epirubicin, in newly diagnosed advanced epithelial ovarian cancer patients. In this trial, patients with histologically proven epithelial ovarian cancer were randomly assigned to receive first-line polychemotherapy with cisplatin/paclitaxel/epirubicin (CEP arm) or cisplatin/paclitaxel/ifosfamide (CIP arm) for six cycles every 21 days. Two hundred and eight patients were randomised between the two treatment arms. The Phase II clinical trial finds were as follows:

  • After a median follow-up of 82 months, median overall survival (OS) was 51 months in the CIP arm, and 65 months in the CEP arm; and
  • 5-year survival rates were 43% in the CIP arm, and 50% in the CEP arm.

The trial investigators note that the OS findings seem longer in duration than is commonly reported, especially considering that more than 50% of the newly diagnosed advanced ovarian cancer patients were suboptimally debulked or cytoreduced after their first surgery. The trial investigators concluded that this unexpected finding might be a consequence of the close surgical surveillance and aggressive chemotherapeutic approach.

[Source: “A phase II randomised clinical trial comparing cisplatin, paclitaxel and ifosfamide with cisplatin, paclitaxel and epirubicin in newly diagnosed advanced epithelial ovarian cancer: long-term survival analysis;” Fruscio R. et. al.; Br J Cancer. 2008 Feb 26;98(4):720-7.]

Comment: Although small in size, this Phase II randomized clinical trial suggests that aggressive surgical intervention followed by aggressive polychemotherapy (involving epirubicin or ifosfamide in tandem with paclitaxel and cisplatin) may increase overall survival in newly diagnosed, advanced-stage ovarian cancer survivors. The findings of at least one major clinical study cite that optimal cytoreduction, as a stand-alone independent factor, provides up to a 50% increase in actuarial survival. In the U.S., an “optimal” cytoreduction is generally defined as a surgical procedure that results in 1 centimeter or less of macroscopic cancer present within the body after surgery. The surprising results of the study discussed above seem to indicate that a suboptimal cytoreduction or debulking surgery followed by aggressive polychemotherapy may be beneficial in extending overall survival in newly diagnosed, advanced-stage ovarian cancer survivors. The issue of what measure should be used to define an “optimal” cytoreduction or debulking is not without controversy with the ovarian cancer arena.