- Email: [email protected]
The case for informative phase 2 trials in osteosarcoma
Comment
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Dearnaley D, Syndikus I, Mossop H, et al, on behalf of the CHHiP Investigators. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol 2016; published online June 20. http://dx.doi.org/http://dx.doi.org/10.1016/ S1470-2045(16)30102-4. Incrocci L, Wortel RC, Alemayehu WG, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2016; published online June 20. http://dx.doi.org/http://dx.doi.org/10.1016/S14702045(16)30070-5. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999; 43: 1095–101. Arcangeli S, Strigari L, Gomellini S, et al. Updated results and patterns of failure in a randomized hypofractionation trial for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2012; 84: 1172–78. Pollack A, Walker G, Horwitz EM, et al. Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer. J Clin Oncol 2013; 31: 3860–68. Aluwini S, Pos F, Schimmel E, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): acute toxicity results from a randomised non-inferiority phase 3 trial. Lancet Oncol 2015; 16: 274–83.
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Aluwini S, Pos F, Schimmel E, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial. Lancet Oncol 2016; 17: 464–74. Lee WR, Dignam JJ, Amin MB, et al. Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol 2016; published online April 4. DOI:10.1200/JCO.2016.67.0448. Wilkins A, Mossop H, Syndikus I, et al. Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol 2015; 16: 1605–16. King CR, Freeman D, Kaplan I, et al. Stereotactic body radiotherapy for localized prostate cancer: pooled analysis from a multi-institutional consortium of prospective phase II trials. Radiother Oncol 2013; 109: 217–21.
Cavallini James/BSIP/Science Photo Library
The case for informative phase 2 trials in osteosarcoma
See Articles page 1070
1022
Osteosarcoma is the most common malignant tumour of the bone but only five cytotoxic chemotherapy drugs—doxorubicin, cisplatin, and high dose methotrexate (MAP), and ifosfamide and etoposide— have been shown to be of benefit. 10-year overall survival is about 60% and has not changed in more than 30 years.1 Consequently, it is imperative to explore the activity of novel agents in osteosarcoma with the goal of improving outcome and, ultimately, if outcome is sufficiently improved and a low-risk group can be identified, decreasing treatment-related morbidity. In The Lancet Oncology, Sophie Piperno-Neumann and colleagues2 present the results of OS2006, a randomised trial of zolendronate in addition to chemotherapy in newly diagnosed osteosarcoma. Unfortunately, the trial showed an absence of improvement in 3-year event-free survival in the zolendronate plus chemotherapy group (57·1% [95% CI 48·8–65·0]) compared with the chemotherapy alone group (63·4% [55·2–70·9], HR 1·36 [95% CI 0·95–1·96]; p=0·094). In fact, trial enrolment was terminated prematurely for futility when an interim analysis found the likelihood of showing benefit to be almost null. Several important lessons can be learned from this and other recently completed phase 3 trials in osteosarcoma. This study was done as a collaboration of three clinical trials groups in France. Despite this cooperative approach
and the so-called non-restrictive eligibility criteria, 7 years were required to accrue 318 patients. As a consequence of the non-restrictive eligibility, there was heterogeneity in the evaluable population; patients could have localised, possible, or definite metastatic disease, axial or appendicular primary tumours, and metastatic sites restricted to the lung or in other sites. Although sensitivity analyses support the authors’ conclusion that a negative trial result is not due to imbalances in the randomised population, it is preferable for outcome analysis to be restricted to a homogeneous patient population. Heterogeneity of the patient population and the duration needed to enrol a sufficient number of patients emphasise the importance of international collaboration for the undertaking of phase 3 trials in osteosarcoma. The EURAMOS-1 trial enrolled 2260 patients over 6 years and outcome analyses were done in a homogenous patient population showing the feasibility of international cooperation in phase 3 trials of osteosarcoma.3,4 Unfortunately, EURAMOS-1, which tested the effect on event-free survival of the addition of ifosfamide and etoposide to MAP in high-risk patients and the addition of interferon to MAP in low-risk patients, showed no benefit to either intervention.5 OS2006 and EURAMOS-1 show that a collaborative effort and a 5–10 year time investment is required to do definitive phase 3 trials in osteosarcoma. In view of www.thelancet.com/oncology Vol 17 August 2016
Comment
this major investment, it is perhaps even more essential than in other cancers that the chances of a successful phase 3 trial be maximised in osteosarcoma. This trial and a previous phase 3 trial of mifamurtide,6 justified by evidence from preclinical laboratory studies, have not resulted in the identification of drugs that are universally accepted for incorporation into first-line osteosarcoma therapy. Thus, one needs to consider whether preclinical evidence suggesting activity of a novel drug in osteosarcoma is sufficient to serve as justification for randomised phase 3 trials. On the other hand, in view of the absence of effective second-line therapies for recurrent osteosarcoma, preclinical evidence could be used as rationale for phase 2 trials. Two other trials assessing the feasibility of adding bisphosphonates to chemotherapy have been done in osteosarcoma but neither were designed to assess patient outcome.7,8 Perhaps a welldesigned phase 2 trial of zolendronate could have shown limited activity in patients with osteosarcoma suggesting this drug not be studied in a phase 3 trial. We have recently proposed a novel approach for phase 2 trial design for recurrent osteosarcoma to facilitate identification of drugs with clinical activity.9 The proposed design takes into account disease features unique to osteosarcoma such as the calcified matrix and the need to both control bulk disease and inhibit metastatic progression. The first of these phase 2 trials completed accrual in 4 months10 and two other clinical trials, of dinutuximab (NCT02484443) and denosumab (NCT02470091), are underway. We acknowledge these comments are made in hindsight and in a drug development environment that is vastly different from the environment that existed when the OS2006 and other mentioned trials were designed. We also admit that the proposed approach is too recent to have been vetted for its ability to identify a novel
agent with activity in osteosarcoma let alone a novel drug that when added to first-line therapy improves outcome. Nevertheless, in osteosarcoma, following a rational progression from preclinical studies to early phase trials to randomised phase 3 trials requiring major investment seems particularly important. *Katherine A Janeway, Richard Gorlick Dana-Farber Cancer Institute, Children’s Hospital Boston, Pediatric Hematology Oncology, Boston, MA 02215, UAS (KAJ); and The Children’s Hospital of Montefiore, Bronx, NY, USA (RG) [email protected] We declare no competing interests. 1
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Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer 2009; 115: 1531–43. Piperno-Neumann S, Le Deley MC, Rédini F, et al. Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multi-centre, open-label, phase 3 trial. Lancet Oncol 2016; published online June 17. http://dx.doi.org/10.1016/ S1470-2045(16)30096-1. Whelan JS, Bielack SS, Marina N, et al. EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment. Ann Oncol 2015; 26: 407–14. Bielack SS, Smeland S, Whelan JS, et al. Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: first results of the EURAMOS-1 good response randomized controlled trial. J Clin Oncol 2015; 33: 2279–87. Marina N, Grier HE, Gorlick R, et al. Randomized comparison of MAPIE vs MAP in patients with a poor response to pre-operative chemotherapy for newly-diagnosed high-grade osteosarcoma: results from the EURAMOS-1 trial. Lancet Oncol (in press). Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children’s Oncology Group. J Clin Oncol 2008; 26: 633–38. Goldsby RE, Fan TM, Villaluna D, et al. Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: a report from the Children’s Oncology Group. Eur J Cancer 2013; 49: 2384–91. Meyers PA, Healey JH, Chou AJ, et al. Addition of pamidronate to chemotherapy for the treatment of osteosarcoma. Cancer 2011; 117: 1736–44. Lagmay JP, Krailo MD, Dang H, et al. Outcome of patients with recurrent osteosarcoma enrolled in seven phase II trials through children’s cancer group, pediatric oncology group, and children’s oncology group: learning from the past to move forward. J Clin Oncol (in press). Isakoff MS, Goldsby R, Villaluna D, et al. Rapid protocol enrollment in osteosarcoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2016; 63: 370–71.
Obinutuzumab plus bendamustine in rituximab-refractory indolent lymphoma Since the advent of rituximab, a chimeric monoclonal antibody directed against CD20, there has been near universal integration of this drug into treatment regimens for B-cell non-Hodgkin lymphomas. In view of rituximab’s ubiquitous implementation as either www.thelancet.com/oncology Vol 17 August 2016
a single drug or in combination with chemotherapy, it was inevitable that a population of rituximabrefractory patients would emerge and pose a therapeutic dilemma for the oncologist. Rituximab refractoriness has been functionally defined, and
Published Online June 23, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30157-7 See Articles page 1081
1023
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Dearnaley D, Syndikus I, Mossop H, et al, on behalf of the CHHiP Investigators. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol 2016; published online June 20. http://dx.doi.org/http://dx.doi.org/10.1016/ S1470-2045(16)30102-4. Incrocci L, Wortel RC, Alemayehu WG, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol 2016; published online June 20. http://dx.doi.org/http://dx.doi.org/10.1016/S14702045(16)30070-5. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999; 43: 1095–101. Arcangeli S, Strigari L, Gomellini S, et al. Updated results and patterns of failure in a randomized hypofractionation trial for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2012; 84: 1172–78. Pollack A, Walker G, Horwitz EM, et al. Randomized trial of hypofractionated external-beam radiotherapy for prostate cancer. J Clin Oncol 2013; 31: 3860–68. Aluwini S, Pos F, Schimmel E, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): acute toxicity results from a randomised non-inferiority phase 3 trial. Lancet Oncol 2015; 16: 274–83.
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Aluwini S, Pos F, Schimmel E, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with prostate cancer (HYPRO): late toxicity results from a randomised, non-inferiority, phase 3 trial. Lancet Oncol 2016; 17: 464–74. Lee WR, Dignam JJ, Amin MB, et al. Randomized phase III noninferiority study comparing two radiotherapy fractionation schedules in patients with low-risk prostate cancer. J Clin Oncol 2016; published online April 4. DOI:10.1200/JCO.2016.67.0448. Wilkins A, Mossop H, Syndikus I, et al. Hypofractionated radiotherapy versus conventionally fractionated radiotherapy for patients with intermediate-risk localised prostate cancer: 2-year patient-reported outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol 2015; 16: 1605–16. King CR, Freeman D, Kaplan I, et al. Stereotactic body radiotherapy for localized prostate cancer: pooled analysis from a multi-institutional consortium of prospective phase II trials. Radiother Oncol 2013; 109: 217–21.
Cavallini James/BSIP/Science Photo Library
The case for informative phase 2 trials in osteosarcoma
See Articles page 1070
1022
Osteosarcoma is the most common malignant tumour of the bone but only five cytotoxic chemotherapy drugs—doxorubicin, cisplatin, and high dose methotrexate (MAP), and ifosfamide and etoposide— have been shown to be of benefit. 10-year overall survival is about 60% and has not changed in more than 30 years.1 Consequently, it is imperative to explore the activity of novel agents in osteosarcoma with the goal of improving outcome and, ultimately, if outcome is sufficiently improved and a low-risk group can be identified, decreasing treatment-related morbidity. In The Lancet Oncology, Sophie Piperno-Neumann and colleagues2 present the results of OS2006, a randomised trial of zolendronate in addition to chemotherapy in newly diagnosed osteosarcoma. Unfortunately, the trial showed an absence of improvement in 3-year event-free survival in the zolendronate plus chemotherapy group (57·1% [95% CI 48·8–65·0]) compared with the chemotherapy alone group (63·4% [55·2–70·9], HR 1·36 [95% CI 0·95–1·96]; p=0·094). In fact, trial enrolment was terminated prematurely for futility when an interim analysis found the likelihood of showing benefit to be almost null. Several important lessons can be learned from this and other recently completed phase 3 trials in osteosarcoma. This study was done as a collaboration of three clinical trials groups in France. Despite this cooperative approach
and the so-called non-restrictive eligibility criteria, 7 years were required to accrue 318 patients. As a consequence of the non-restrictive eligibility, there was heterogeneity in the evaluable population; patients could have localised, possible, or definite metastatic disease, axial or appendicular primary tumours, and metastatic sites restricted to the lung or in other sites. Although sensitivity analyses support the authors’ conclusion that a negative trial result is not due to imbalances in the randomised population, it is preferable for outcome analysis to be restricted to a homogeneous patient population. Heterogeneity of the patient population and the duration needed to enrol a sufficient number of patients emphasise the importance of international collaboration for the undertaking of phase 3 trials in osteosarcoma. The EURAMOS-1 trial enrolled 2260 patients over 6 years and outcome analyses were done in a homogenous patient population showing the feasibility of international cooperation in phase 3 trials of osteosarcoma.3,4 Unfortunately, EURAMOS-1, which tested the effect on event-free survival of the addition of ifosfamide and etoposide to MAP in high-risk patients and the addition of interferon to MAP in low-risk patients, showed no benefit to either intervention.5 OS2006 and EURAMOS-1 show that a collaborative effort and a 5–10 year time investment is required to do definitive phase 3 trials in osteosarcoma. In view of www.thelancet.com/oncology Vol 17 August 2016
Comment
this major investment, it is perhaps even more essential than in other cancers that the chances of a successful phase 3 trial be maximised in osteosarcoma. This trial and a previous phase 3 trial of mifamurtide,6 justified by evidence from preclinical laboratory studies, have not resulted in the identification of drugs that are universally accepted for incorporation into first-line osteosarcoma therapy. Thus, one needs to consider whether preclinical evidence suggesting activity of a novel drug in osteosarcoma is sufficient to serve as justification for randomised phase 3 trials. On the other hand, in view of the absence of effective second-line therapies for recurrent osteosarcoma, preclinical evidence could be used as rationale for phase 2 trials. Two other trials assessing the feasibility of adding bisphosphonates to chemotherapy have been done in osteosarcoma but neither were designed to assess patient outcome.7,8 Perhaps a welldesigned phase 2 trial of zolendronate could have shown limited activity in patients with osteosarcoma suggesting this drug not be studied in a phase 3 trial. We have recently proposed a novel approach for phase 2 trial design for recurrent osteosarcoma to facilitate identification of drugs with clinical activity.9 The proposed design takes into account disease features unique to osteosarcoma such as the calcified matrix and the need to both control bulk disease and inhibit metastatic progression. The first of these phase 2 trials completed accrual in 4 months10 and two other clinical trials, of dinutuximab (NCT02484443) and denosumab (NCT02470091), are underway. We acknowledge these comments are made in hindsight and in a drug development environment that is vastly different from the environment that existed when the OS2006 and other mentioned trials were designed. We also admit that the proposed approach is too recent to have been vetted for its ability to identify a novel
agent with activity in osteosarcoma let alone a novel drug that when added to first-line therapy improves outcome. Nevertheless, in osteosarcoma, following a rational progression from preclinical studies to early phase trials to randomised phase 3 trials requiring major investment seems particularly important. *Katherine A Janeway, Richard Gorlick Dana-Farber Cancer Institute, Children’s Hospital Boston, Pediatric Hematology Oncology, Boston, MA 02215, UAS (KAJ); and The Children’s Hospital of Montefiore, Bronx, NY, USA (RG) [email protected] We declare no competing interests. 1
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8 9
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Mirabello L, Troisi RJ, Savage SA. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer 2009; 115: 1531–43. Piperno-Neumann S, Le Deley MC, Rédini F, et al. Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multi-centre, open-label, phase 3 trial. Lancet Oncol 2016; published online June 17. http://dx.doi.org/10.1016/ S1470-2045(16)30096-1. Whelan JS, Bielack SS, Marina N, et al. EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment. Ann Oncol 2015; 26: 407–14. Bielack SS, Smeland S, Whelan JS, et al. Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: first results of the EURAMOS-1 good response randomized controlled trial. J Clin Oncol 2015; 33: 2279–87. Marina N, Grier HE, Gorlick R, et al. Randomized comparison of MAPIE vs MAP in patients with a poor response to pre-operative chemotherapy for newly-diagnosed high-grade osteosarcoma: results from the EURAMOS-1 trial. Lancet Oncol (in press). Meyers PA, Schwartz CL, Krailo MD, et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival—a report from the Children’s Oncology Group. J Clin Oncol 2008; 26: 633–38. Goldsby RE, Fan TM, Villaluna D, et al. Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: a report from the Children’s Oncology Group. Eur J Cancer 2013; 49: 2384–91. Meyers PA, Healey JH, Chou AJ, et al. Addition of pamidronate to chemotherapy for the treatment of osteosarcoma. Cancer 2011; 117: 1736–44. Lagmay JP, Krailo MD, Dang H, et al. Outcome of patients with recurrent osteosarcoma enrolled in seven phase II trials through children’s cancer group, pediatric oncology group, and children’s oncology group: learning from the past to move forward. J Clin Oncol (in press). Isakoff MS, Goldsby R, Villaluna D, et al. Rapid protocol enrollment in osteosarcoma: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2016; 63: 370–71.
Obinutuzumab plus bendamustine in rituximab-refractory indolent lymphoma Since the advent of rituximab, a chimeric monoclonal antibody directed against CD20, there has been near universal integration of this drug into treatment regimens for B-cell non-Hodgkin lymphomas. In view of rituximab’s ubiquitous implementation as either www.thelancet.com/oncology Vol 17 August 2016
a single drug or in combination with chemotherapy, it was inevitable that a population of rituximabrefractory patients would emerge and pose a therapeutic dilemma for the oncologist. Rituximab refractoriness has been functionally defined, and
Published Online June 23, 2016 http://dx.doi.org/10.1016/ S1470-2045(16)30157-7 See Articles page 1081
1023