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Two Consecutive Phase II Window Trials of Irinotecan Alone or in Combination With Vincristine for the Treatment of Metastatic Rhabdomyosarcoma: The Children's Oncology Group

Alberto S. Pappo, Elizabeth Lyden, Phillip Breitfeld, Sarah S. Donaldson, Eugene Wiener, David Parham, Kristine R. Crews, Peter Houghton, William H. Meyer

From the Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX; Department of Preventive and Societal Medicine, University of Nebraska Medical Center, Omaha, NE; Duke University Medical Center, Durham, NC; Stanford University Medical Center, Stanford, CA; Children's Hospital of Pittsburgh, Pittsburgh, PA; University of Arkansas, Little Rock, AR; St Jude Children's Research Hospital, Memphis, TN; and the University of Oklahoma Health Science Center, Oklahoma City, OK

Address reprint requests to Alberto S. Pappo, MD, Texas Children’s Cancer Center, Baylor College of Medicine, 6621 Fannin St, MC CC 1510.00, Houston, TX 77030; e-mail: aspappo{at}txccc.org

	ABSTRACT

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Purpose: To estimate the antitumor activity and toxicity of irinotecan alone and in combination with vincristine when administered as window therapy and in combination with standard chemotherapy in pediatric patients with newly diagnosed metastatic rhabdomyosarcoma.

Patients and Methods: Nineteen patients younger than age 21 years with newly diagnosed metastatic rhabdomyosarcoma or undifferentiated sarcoma received window therapy with two cycles of irinotecan (20 mg/m² daily for 5 days, repeated for 2 weeks) and 50 patients received window therapy with vincristine 1.5 mg/m² (weeks 0, 1, 3, and 4) and two cycles of irinotecan (20 mg/m² daily for 5 days, repeated for 2 weeks). Patients who achieved a partial response (PR) or complete response (CR) received these agents alternating with vincristine (V; 1.5/mg/m²), dactinomycin (A; 1.5 mg/m²), and cyclophosphamide (C; 2.2 g/m²) during weeks 6 through 41. Nonresponders were treated with VAC alone. Radiotherapy was administered to sites of disease at weeks 15 to 21.

Results: The window response rate (PR/CR) for patients who received irinotecan was 42% (95% CI, 38% to 80%) but the high progressive disease (PD) rate of 32% (95% CI, 11% to 52%) prompted closure of the trial. The window CR/PR rate for patients who received vincristine and irinotecan was 70% (95% CI, 57% to 83%), and the PD rate was only 8%. GI toxicities (abdominal pain, diarrhea, dehydration) were the most common adverse effects associated with the administration of irinotecan.

Conclusion: The combination of vincristine and irinotecan is highly active in metastatic rhabdomyosarcoma. The different mechanism of action and nonoverlapping toxicity profile with VAC makes this combination an attractive candidate for further testing in intermediate risk patients with rhabdomyosarcoma.

	INTRODUCTION

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Cure rates continue to be suboptimal for patients with high-risk metastatic rhabdomyosarcoma, with less than one fourth of these patients expected to survive.¹ Despite multiple strategies to improve outcome such as dose intensification² and the addition of active agents including doxorubicin, survival has remained unchanged over the last 30 years.³ The Soft Tissue Sarcoma Committee of the Children's Oncology Group (STS-COG) has used the preclinical xenograft model to identify novel drugs and facilitate pharmacokinetic monitoring of new agents against childhood rhabdomyosarcoma.^4-6 This model has identified many single agents and combinations.^4,6-8 More recently, irinotecan, a prodrug that is activated by carboxylesterases to SN-38, the active topoisomerase I poison has shown marked preclinical activity against pediatric rhabdomyosarcoma xenografts, particularly when low-dose protracted schedules are used.^9-11 A phase I trial of intravenous irinotecan administered daily for 10 days (daily for 5 days, repeated for 2 weeks) in pediatric patients with relapsed solid tumors identified irinotecan as an active agent in rhabdomyosarcoma. Diarrhea was a dose-limiting toxicity, and the recommended phase II dose was 20 mg/m² per day.⁹ Subsequently, the STS-COG conducted a phase II window study of irinotecan in patients with metastatic rhabdomyosarcoma, but due to a high rate of disease progression, the trial was closed after the first stage of evaluation. Additional preclinical information from the xenograft model prompted us to add vincristine to irinotecan.¹² This article summarizes the results of these two consecutive trials.

	PATIENTS AND METHODS

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Irinotecan Window Alone (D9802)
Eligibility criteria included newly diagnosed metastatic rhabdomyosarcoma, undifferentiated sarcoma, or ectomesenchymoma; age younger than 21 years, normal serum creatinine and bilirubin; absolute neutrophil count more than 1,500/mm³ and platelet count more than 150,000/mm³ (unless there was bone marrow infiltration with tumor); and no prior chemotherapy. Therapy must have started within 42 days of the surgical procedure that established the diagnosis, and signed informed consent and institutional review board approval of the protocol were also required. Exclusion criteria included prior treatment (except corticosteroids); parent/patient refusal; patients with metastatic embryonal tumors who were younger than 10 years; pregnancy or active breast feeding by the patient; and a parameningeal primary tumor with evidence of base of skull erosion and/or intracranial extension or cranial nerve palsy. Phase I institutions were encouraged to participate in pharmacokinetic studies. Pretreatment investigations included a CBC, differential, platelet count, urinalysis, creatinine, blood urea nitrogen, alkaline phosphatase, lactate dehydrogenase (LDH), electrolytes, calcium, phosphorus, total protein, albumin, bone marrow aspirate and biopsy, magnetic resonance imaging (MRI) or computed tomography (CT) of the primary tumor, CT of the chest, chest x-ray, CT or ultrasound of the liver (for patients with abdominal pelvic tumors), MRI or CT of the head (for patients with CNS symptoms at diagnosis), CT or ultrasound of the retroperitoneum (for lower extremity tumors), and bone scan.

Irinotecan and Vincristine Window (D9802R)
Eligibility criteria were similar to those specified for D9802 except that all eligible patients were discussed with the study chair to determine eligibility. Patients with abnormal bone scans in the skull, neck, vertebrae or with evidence of paraspinal disease were required to have a brain or spine MRI. Patients younger than 50 years of age were allowed to be registered as of July 19, 2002 (to encourage adult participation), and coagulation profile was required for all patients. Patients with potentially life-threatening tumors (renal obstruction or airway obstruction) were excluded from the window trial.

Treatment
Irinotecan window (D9802). Patients received two cycles of irinotecan (20 mg/m²) intravenously over 60 minutes daily for 5 days, followed by 2 days of rest, and then a total of 5 more days (daily x 5 x 2) on weeks 0, 1, 3, and 4 (Fig 1). Response was evaluated after two cycles at week 5. For consenting patients at phase I institutions, pharmacokinetic studies were performed (discussed further herein). The risk of diarrhea and abdominal pain, as well as the use of loperamide to treat these symptoms, were discussed in advance.¹³ For patients with stable or progressive disease after two cycles of irinotecan, therapy was switched to vincristine (V; 1.5 mg/m²), dactinomycin (A; 1.5 mg/m²), and cyclophosphamide (C; 2.2 g/m²) with Mesna 440 mg/m² at hours 0, 3, 6, and 9 followed by granulocyte colony-stimulating factor (G-CSF) 5 µg/kg subcutaneously for at least 7 days. VAC was delivered at weeks 6, 9, 12, 23, 26, 29, 32, 35, 38, and 41. In addition, vincristine alone was administered at weeks 7, 8, 10, 11, 13, 15, 17, 18, 24, 27, 33, and 34. Radiotherapy to primary and metastatic sites was administered from weeks 15 to 22 when only vincristine and cyclophosphamide were administered. The volume irradiated included the extent of tumor at the time of diagnosis and a minimum margin of 2 cm. Recommended doses were 50.4 Gy for sites of gross disease and 41.4 Gy for sites of microscopic disease, administered in 1.8-Gy daily fractions. Patients ineligible or who refused the window were treated with VAC alone starting at week 0. Patients with a partial or complete response after irinotecan received alternating courses of VAC (weeks 6, 12, 23, 29, 35, and 41) and V (1.5 mg/m²) and irinotecan (20 mg/m² daily x 5 x 2) at weeks 9, 10, 26, 27, 32, 33, 38, and 39. Patients who did not respond or progressed during the window portion of the trial were treated with VAC from weeks 6 through 41 (Fig 1).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Treatment schema for protocol D9802 (irinotecan window). "Daily x 5" indicates "daily for 5 consecutive days." PK, pharmacokinetic studies; CPT, irinotecan 20 mg/m2/daily x 5 x 2 intravenously (IV) after vincristine; V, vincristine 1.5 mg/m2 (max 2.0 mg) x 1 IV; A, dactinomycin 1.5 mg/m2 (max 2.5 mg) x 1 IV; C, cyclophosphamide 2.2 g/m2 x 1 IV, followed by Mesna 440 mg/m2 given via infusion 15 minutes prior to cyclophosphamide and 3, 6, and 9 hours after cyclophosphamide; G-CSF, granulocyte colony-stimulating factor.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Treatment schema for protocol D9802R (vincristine and irinotecan window). "Daily x 5" indicates "daily for 5 consecutive days." (A) Pharmacokinetic studies (PK) done after dose 1 of irinotecan on day 1 of week 0; irinotecan (CPT) 20 mg/m2 intravenously (maximum dose 40 mg/day) over 60 minutes daily x 5, rest 2 days, resume daily x 5.

Pharmacokinetics
We performed pharmacokinetic studies of irinotecan on day 1 of week 0 for patients on D9802 and D9802R. For D9802 patients, studies were repeated on day 1 of week 9 (vincristine and irinotecan). Irinotecan pharmacokinetics and its metabolites SN-38, and SN-38 glucuronide (SN-38G) were evaluated before the infusion, and at 0.25, 0.5, 1, 2, 4, and 6 hours following the infusion. Plasma concentrations of the lactone and carboxylate forms of irinotecan, SN-38, and SN-38G were assessed by high-performance liquid chromatography with fluorescence detection as previously described.¹⁵

Response Definitions
Response was assessed at week 5 after 2 cycles of irinotecan (D9802) or vincristine and irinotecan (D9802R). Other scheduled evaluations were performed at weeks 14, 25, and 44. Complete response was defined as disappearance of all tumors, partial response as a decrease of at least 50% in the sum of the products of the maximum perpendicular diameters of all measurable lesions, and stable disease as less than 50% decrease in the sum of all products of the maximum perpendicular diameters of all measurable lesions. Progressive disease was defined as a more than 25% increase in the sum of all the products of the maximum perpendicular diameters of measurable lesions or the appearance of new lesions. Toxicity was evaluated using the Common Toxicity Criteria version 2.0 of the National Cancer Institute (National Institutes of Health, Bethesda, MD). Patients with clinical and radiographic evidence of progression at week 3 were switched to VAC, as were patients with stable or progressive disease at week 5. Off-study criteria included disease progression at week 3 or 5, stable disease or disease progression at week 14, disease progression or recurrence at week 25, patient death, patient loss to follow-up, if patients were entered onto another COG therapeutic study, or if patients withdrew consent for any further data collection.

Statistics
D9802 (irinotecan alone) followed a two-stage phase II design. Eighteen patients were initially evaluated; if fewer than eight responses were observed, accrual was to be stopped based on the conclusion that irinotecan had insufficient activity. If eight or more responses were seen, accrual was to continue until 46 patients were enrolled. At least 23 responses were required to declare irinotecan active. Using this study design, the chance of declaring irinotecan active when the true response rate was 40% was 10%, and the chance of concluding that it was insufficiently active when the true response rate was 60% was 10% (a power of 90%). All patients were followed for survival time and disease-free time. For D9802R (vincristine and irinotecan), a similar design was used, but this trial allowed for early termination if either the true response rate was too low (< 40%) or if the true progression rate was too high (> 35%). Eighteen patients were entered in the first stage. If the response rate was seven patients or fewer, or if progression was documented in six or more patients, accrual would stop. Otherwise, accrual would continue, and an additional 26 patients would be enrolled to the second stage (total of 46 patients). If the observed response rate was 22 (48%) of 46 or less, or the progression rate was 12 (26%) of 46 or more, the combination would be considered uninteresting. This study design leads to consideration of further testing 85% of the time when the true response rate is 60% or higher and the true progression rate is 15% or lower. All patients were followed for survival time and time to first event. Failure-free survival (FFS) was defined as the time from study entry to the first occurrence of recurrent disease after window therapy, a second cancer, or death as a first event. Progression during window therapy did not constitute an event for the computation of event-free survival. Survival was defined as the time from study entry until death as a result of any cause. Patients not experiencing an event were censored at their date of last contact. Estimates of the time to the event distributions were calculated using the Kaplan-Meier method.¹⁶

	RESULTS

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Irinotecan Window D9802
From September 1999 to November 2000, 41 eligible patients were entered: 22 in the irinotecan arm and 19 in the VAC arm. Five patients were declared ineligible (three in the irinotecan arm and two in the VAC arm) because of incorrect diagnosis (n = 4) and spinal cord compression at the time of diagnosis (n = 1). The characteristics of the 36 eligible patients are shown in Table 2. There were no significant differences in characteristics between patients treated in the irinotecan and VAC arms. The response rate among the 19 patients who received irinotecan was 42% (95% CI, 20% to 64%). However, six patients (32%; 95% CI, 11% to 52%) experienced progressive disease, prompting closure of the irinotecan window arm (Table 3). The most common grade 3 to 4 toxicities are depicted in Table 4.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Kaplan-Meier estimate of failure-free survival for 19 patients enrolled on D9802 (irinotecan alone). CNSR, censored; CPT-11, irinotecan; VAC, vincristine 1.5/mg/m2, dactinomycin 1.5 mg/m2, and cyclophosphamide 2.2 g/m2.

The most frequent grade 3 and 4 toxicities are depicted in Table 4. After the first and second course of vincristine and irinotecan, 52% and 43% of patients, respectively, experienced one or more grade 3 or 4 toxicities. In contrast, 83% and 91% of VAC patients, respectively experienced such events. Patients who received vincristine and irinotecan most commonly experienced GI toxicities (abdominal pain, diarrhea, dehydration), whereas VAC-treated patients most often exhibited hematologic toxicities and febrile neutropenia.

Median follow-up for this cohort is presently 1.1 year. The estimated 1- and 2-year FFS rates were 65% (95% CI, 49% to 77%), and 23% (95% CI, 9% to 40%), respectively, and survival rates estimated were 71% (95% CI, 55% to 83%) and 52% (95% CI, 30% to 69%), respectively (Fig 4), and were similar to those of patients treated with VAC alone. The majority of relapses were distant (60%).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Kaplan-Meier estimate of failure-free survival for 50 patients enrolled on D9802R (vincristine and irinotecan). CNSR, censored; CPT-11, irinotecan; VAC, vincristine 1.5/mg/m2, dactinomycin 1.5 mg/m2, and cyclophosphamide 2.2 g/m2.

	DISCUSSION

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The unexpectedly high rate of progression seen with irinotecan alone precludes us from recommending the use of this single agent for the treatment of rhabdomyosarcoma. In retrospect, similar rates of progression have been reported in other window studies of rhabdomyosarcoma that incorporated topotecan and high-dose methotrexate.^7,18 Although it is unclear whether the chance for cure for nonresponding patients was sacrificed, we believe that future window trials must incorporate appropriate monitoring rules for progression of newly diagnosed patients with metastatic malignancies such as those incorporated in our second study.

The main adverse effects of the irinotecan and vincristine combination were confined to the GI tract. Among these, diarrhea and abdominal pain leading to dehydration and electrolyte abnormalities predominated. Severe grade 3 to 4 toxicities were less frequent in patients who received this combination versus in those who received VAC (approximately 50% v > 80%). A recent study conclusively showed that adding cefixime significantly decreases the incidence of GI toxicities in patients receiving oral irinotecan, allowing higher doses to be administered.¹⁹ In our second trial, further episodes of diarrhea were prevented in two patients who experienced grade 3 to 4 toxicity with the first cycle of vincristine and irinotecan by adding cefixime during their second cycle of chemotherapy. Future trials should consider the use of cefixime to prevent severe GI toxicity.

The median SN-38 AUC achieved in our patients was clinically relevant and similar to that achieved in other trials of irinotecan administered at the maximum-tolerated dose of 20 mg/m²/d.^9,20 No pharmacokinetic interaction was observed between irinotecan and vincristine.

Despite the promising response rate seen with vincristine and irinotecan, we were unable to document an improvement in survival. We acknowledge that our trial was not designed to detect such an effect, and therefore postulate that other factors might explain the lack of difference in survival. For example, the combination of irinotecan and vincristine might target a similar population of tumor cells as those targeted by standard agents such as cyclophosphamide or vincristine. Perhaps the compounds used in our phase II window studies affect only a subpopulation of stem cells that lack a metastatic phenotype.²¹ This scenario could explain the successful integration of etoposide and ifosfamide and the effect of this combination on survival in nonmetastatic Ewing sarcoma.²² Another possibility is that increased exposure to vincristine and irinotecan during continuation therapy may have improved patient outcome. A prospective trial of vincristine and irinotecan with VAC is being planned by our committee to better define the role of this drug combination in the treatment of rhabdomyosarcoma.

In summary, vincristine and irinotecan is a highly active combination against rhabdomyosarcoma. This drug pair is non–cross resistant and has a nonoverlapping toxicity profile with VAC; therefore, its integration into current front-line regimens for the treatment of rhabdomyosarcoma appears warranted.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: N/A Research Funds: Peter Houghton, Pfizer Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Alberto S. Pappo, Elizabeth Lyden, Eugene Wiener, Kristine R. Crews, Peter Houghton, William H. Meyer

Administrative support: William H. Meyer

Collection and assembly of data: Alberto S. Pappo, Elizabeth Lyden, David Parham, Kristine R. Crews

Data analysis and interpretation: Alberto S. Pappo, Elizabeth Lyden, Philip Breitfeld, David Parham, Kristine R. Crews, William H. Meyer

Manuscript writing: Alberto S. Pappo, Elizabeth Lyden, Sarah S. Donaldson, Kristine R. Crews, William H. Meyer

Final approval of manuscript: Alberto S. Pappo, Elizabeth Lyden, Philip Breitfeld, Sarah S. Donaldson, Eugene Wiener, David Parham, Kristine R. Crews, Peter Houghton, William H. Meyer

	NOTES

 
Supported by Grants No. U10 CA 98543, CA 13539, and CA 30969.

Presented in part in abstract form at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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Submitted April 24, 2006; accepted November 10, 2006.

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