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.
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
- A phase II trial of SNS-595 in women with platinum resistant epithelial ovarian cancer (2008 ASCO Abstract #5582). Refer to Voreloxin (SNS-595) Produces 48% Disease Stabilization in Treatment Resistant Ovarian Cancer Patients, H*O*P*E* weblog post, May 31, 2008.
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]
- NOV-002 and Carboplatin Slow Disease Progression of Platinum Drug Resistant Ovarian Cancer, H*O*P*E* weblog post, April 3, 2008.
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]
- Poniard Announces Positive Efficacy and Safety Data From Phase 1 Trial of Picoplatin in Multiple Tumor Types Including Ovarian Cancer, EarthTimes.org Press Release, June 1, 2008 (“In a previous Phase 2 study of picoplatin monotherapy in platinum-pretreated ovarian cancer patients, disease control was achieved in 57 percent of 82 evaluable patients: 8 patients had a complete response, 7 had a partial response and 32 experienced disease stabilization”).
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:
- A phase IIa study of a sequential regimen using azacitidine to reverse platinum resistance to carboplatin in patients with platinum resistant or refractory epithelial ovarian cancer (2008 ASCO Annual Mtg. Abstr. #3500). Remarkably, our regimen resulted in 1CR, 3 PR (RR: 14%) and 10 SD in 29 evaluable patients, which is in stark contrast to no responses to a carboplatin-based regimen in a similar cohort of patients in the same institution. The median duration of response was 7.5 months. OS at 1-yr was 53%. Patients classified as having platinum resistant disease had an objective response of 22% and one-year OS of 67% compared to 0% and 33% in platinum refractory patients, respectively. Conclusions: To the best of our knowledge, this is the first phase II trial in epithelial ovarian cancer patients that demonstrates the ability of a hypomethylating agent (i.e., azacitidine) to reverse platinum resistance. Based on these data, a randomized phase III trial in patients with platinum-resistant epithelial ovarian cancer is warranted. [48% disease control (CR+PR+SD) rate among evaluable patients]
Combretastatin A4 Phosphate (Zybrestat™) and Bevacizumab (Avastin™):
- A phase I study of combretastatin A4 phosphate (CA4P) and bevacizumab in subjects with advanced solid tumors (2008 ASCO Annual Mtg. Abstr. #3550). No partial responses were seen. 9/14 patients experienced disease stabilization for > 12 weeks. 3 patients experienced disease stabilization for > 24 weeks with 2 of these on-going at 47 and 29 weeks respectively at time of data cutoff. DCE-MRI showed statistically significant reductions in tumor perfusion/vascular permeability which reversed after CA4P alone but which were sustained following bevacizumab). [64% disease control (CR+PR+SD) rate among evaluable patients]
- OXiGENE Reports Positive Results in Phase 2 Study of ZYBRESTATTM in Platinum-Resistant Ovarian Cancer.
- New Vascular Disrupting Agent In Combination With Avastin Produces a 64% Disease Stabilization Rate in a Small Phase I Solid Tumor Clinical Trial, H*O*P*E*™ Weblog Post, June 15, 2008.
- A phase IB study evaluating BSI-201 in combination with chemotherapy in subjects with advanced solid tumors (2008 ASCO Annual Mtg. Abstr. #3579). Fifty-five subjects with advanced solid tumors have been treated with BSI-201 doses of 1.1 thru 8.0 mg/kg, in combination with cytotoxic chemotherapy. All dose combinations were well tolerated with a total of 21 serious adverse events reported for 10 trial participants, none of which were deemed related to study drug. A CR at 6 months was reported for 1 subject with ovarian cancer, and 5 subjects with renal, breast (2), uterine, and sarcoma experienced a PR. An additional 19 subjects had SD for 2 months or more. [45% disease control (CR+PR+SD) rate among evaluable patients]
- First in human phase I study of BSI-201, a small molecule inhibitor of poly ADP-ribose polymerase (PARP) in subjects with advanced solid tumors (2008 ASCO Annual Mtg. Abstr. #3577). Best response of SD for 2 months or more was seen for 6/23 patients in this heavily pre-treated population (mean # of prior treatment regimens > 6), with 1 subject on study for over 9 months. [26% disease control (CR+PR+SD) rate among evaluable patients]
- A phase II trial of the histone deacetylase inhibitor belinostat (PXD101) in patients with platinum resistant epithelial ovarian tumors and micropapillary/borderline (LMP) ovarian tumors. A PMH phase II consortium trial (2008 ASCO Annual Mtg. Abstr. #5518 ). Eighteen patients with EOC, median age 59.5 (range 31-78 ) years received a total of 50 cycles of treatment, median no. per patient 2 (range 1 to 8). Nine patients have SD, 6 patients have DP, 3 patients are non evaluable and 2 remain on study [60% disease control (CR+PR+SD) rate among evaluable patients].
- A phase II study of sunitinib (SU11248 ) in patients (pts) with recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma – NCIC CTG IND 185 (2008 ASCO Annual Mtg. Abstr. #5522). Seventeen (16 eligible) pts have been accrued; Median age 55 years (range 41-82 ); tumor histology – 3 pts. with adeno, 1 pt. with endometrioid, 12 pts. with serous; 12 pts had 2 prior chemo regimens; total number of cycles 42, median 3 (range 1 – 5 ). PR has been seen in 2 pts, SD in 10 pts. (range 2.6-6.9 months), PD in 4. Notably, by size criterion alone 4 pts had tumor decrease > 30% but two developed effusions and were therefore catagorized as PD by RECIST; a further 9 pts. had decrease <30% measurable disease. Of 11 pts evaluable for CA125 response, 6 pts. were responders (3 pts. confirmed, 3 pts. unconfirmed), and 5 pts. were non-responders. [75% disease control (CR+PR+SD) rate among evaluable patients]
- 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™):
- Gemcitabine (G) and epirubicin (E) combination, in platinum-resistant or refractory advanced ovarian cancer (PROC) patients: Results of a multicentric phase II trial (2008 ASCO Annual Mtg. Abstr. #5566). All patients were pretreated with 1-4 regimens ( median 1.5). The median platinum-free interval was 5 months (range 0-12). Among 48 evaluable patients (1 lost after the first course and 1 too early), 1 CR and 20 PR were observed, with an overall RR of 43.75%. Moreover, 16 patients (33.3%) presented with SD. The median PFS was 7 months and the 1-year OS was 67.6%. Beside alopecia in all patients, major G3-G4 toxicities consisted of: anemia 4%, neutropenia 56%, thrombocytopenia 6%, vomiting 4%, diarrhoea 2%, liver 8%, mucositis 6% alopecia. No life threatening events occurred. Conclusions: It appears from our experience, that the GE combination is active in these pretreated patients, with a manageable toxicity profile. [77% disease control (CR+PR+SD) rate among evaluable patients]
Belinostat/PXD101, Carboplatin (Paraplatin®) & Paclitaxel (Taxol™):
- Phase II multicenter trial of the histone deactylase inhibitor (HDACi) belinostat, carboplatin and paclitaxel (BelCaP) in patients (pts) with relapsed epithelial ovarian cancer (EOC) (2008 ASCO Annual Mtg. Abstr. #5519). (Accrual was completed in Dec 2007 (# of pts.=35); median age was 60 years (range 39 -80). Pts had received a median of 3 prior treatment regimens (range 1-4). All pts had prior platinum therapy; median platinum-free interval was 12.5 months(range 0.6-60 months), and 11 patients (31%) had relapsed within 6 months of first platinum therapy. Pts received a median of 4 cycles (range 1-13) of BelCaP; 17 patients continue on therapy. Overall pts response was 31%, including 1 CR and 10 PR. In addition, 16 pts (46%) had SD: 11 of these pts had documented tumor shrinkage up to 36%, and 2 pts. had PR pending confirmation [77% disease control (CR+PR+SD) rate among evaluable patients].
Pegylated Liposomal Doxorubicin (Doxil®) & Gemcitabine (Gemzar®):
- A phase I study of pegylated liposomal doxorubicin + gemcitabine in a fixed dose-rate infusion for the treatment of patients with recurrent ovarian cancer (2008 ASCO Annual Mtg. Abstr. #5579). Activity appears to be promising: 30.7% (4/13 patients) OR in pts. with platinum refractory ovarain cancer OC (platinum-free interval < 6 months) and 85.8% (6/7 patients) OR in pts with a platinum-free interval between 6-12 months. [30% and 85% disease control (CR+PR+SD) rate with respect to platinum refractory OC and platinum resistant OC, respectively].
- A phase II evaluation of pemetrexed (LY231514, IND #40061) in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: A study of the gynecologic oncology group (2008 ASCO Annual Mtg. Abstr. #5524). The purpose of the study was to estimate the anti-tumor activity of pemetrexed (LY231514) in patients with persistent or recurrent platinum-resistant epithelial ovarian or primary peritoneal cancer who have failed on higher priority treatment protocols and to determine the nature and degree of toxicity of pemetrexed in this cohort of patients. From July 6, 2004 to August 23, 2006, 51 patients were entered by 15 member institutions of the GOG. Overall, the treatment was well tolerated. More serious toxicities (G3 and G4) included neutropenia in 42%, leukopenia in 25%, anemia in 15%, and constitutional in 15%. No treatment-related deaths were reported. One patient (2%) had a CR and nine patients (19%) had PR with a median duration response of 6.8 months. Seventeen patients (35%) had SD for a median of 4.1 months. Eighteen patients (38%) had DP. Three patients (6%) were inevaluable. Median PFS was 3.0+ months and OS was 11.4+ months. Conclusion: Pemetrexed has demonstrated activity in the treatment of recurrent platinum resistant ovarian carcinoma at the dose and schedule tested [60% disease control (CR+PR+SD) rate among evaluable patients].
- 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:
- Cisplatin-based combination chemotherapy consisting of ifomide, epirubicin, and cisplatin (IEP) is effective for patients with relapsed ovarian carcinoma (ROC) resistant or refractory to TC (paclitaxel/carboplatin) (2008 ASCO Annual Mtg. Abstr. #16507). The purpose of the study was to evaluate the efficacy and toxicity of IEP for patients (pts) with relapsed EOC. Methods: Eligible pts had histologically-confirmed serous, endometrioid, or transitional cell carcinoma of the ovary measuring more than 2 cm in diameter, age < 75 yrs, World Health Organization performance status < 3, adequate pulmonary, cardiac, hematopoietic, liver and renal functions, and written informed consent. Results: Forty eligible pts were enrolled in this study. The median age was 51 yrs (range, 41-64). All pts received more than 6 cycles of TC. Thirty- four of 40 pts (85%) had 1 or more previous chemotherapy other than TC. Histologic types were serous (33 pts), endometrioid (5 pts), and transitional (2 pts). After a median of 4 cycles (range, 2-10), we observed OR in 28 pts (70%), with 4 (10%) CRs and 24 (60%) PRs, and 12 (30%) SD. Median OS for all 40 pts was 24.3 months (mo) (range, 4 to 78). Median OS of pts achieving CR, PR, and SD were ‘not reached”, 23.6 months, 8.2 months, respectively (Log-rank, p < 0.001). The most frequent G3-G4 hematologic toxicities were; neutropenia 57.8%, anemia 43.3%, and thrombocytopenia 14.4%. Alopecia (G1-G2) occurred in 91.3%, but there was no G2 or G3 peripheral neuropathy, nephrotoxicity, or cardiotoxicity. Conclusion: IEP regimen has significant anti-tumor activity with acceptable toxicity and appreciable response duration. Several studies have demonstrated that cisplatin is more effective than carboplatin in almost all platinum-sensitive disease except OC (Lokich J: Cancer Invest 19: 756, 2001). In OC, carboplatin was demonstrated equal to cisplatin in anti-tumor response in optimal disease (GOG 158, AGO), but the equivalency was not demonstrated in suboptimal disease. We must reappraise cisplatin as an agent that should be included in the first line for platinum-sensitive OC. [100% disease control (CR+PR+SD) rate among evaluable patients for platinum-sensitive OC (ie., recurrence 12 months or more after completion of first-line platinum drug treatment)]
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.
- 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.
- 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.