INTRAVENOUS REOLYSIN IN BONE INTRAVENOUS REOLYSIN IN BONE AND SOFT TISSUE SARCOMA AND SOFT TISSUE SARCOMA

METASTATIC TO LUNGMETASTATIC TO LUNG

M Mita, MD, MScM Mita, MD, MScClinical InvestigatorClinical Investigator

Assistant Professor of Medicine, Assistant Professor of Medicine, IDD at CTRC/UTHSCSA IDD at CTRC/UTHSCSA

San AntonioSan Antonio

BACKGROUNDBACKGROUND

Reolysin (reovirus serotype 3)Reolysin (reovirus serotype 3)– Dearing strain, naturally occurring, ubiquitous, Dearing strain, naturally occurring, ubiquitous,

non-enveloped human reovirusnon-enveloped human reovirus– Genome 10 segments of double-stranded Genome 10 segments of double-stranded

RNARNA– Community-acquired infection is mild and Community-acquired infection is mild and

limited to the upper respiratory and GI tract. limited to the upper respiratory and GI tract. – Virus replicates specifically in transformed Virus replicates specifically in transformed

cells possessing an activated Ras pathway. cells possessing an activated Ras pathway.

BACKGROUNDBACKGROUND

– The preferential lysis of cells with activated Ras pathway The preferential lysis of cells with activated Ras pathway

by reovirus appears to be due to the inhibition of double-by reovirus appears to be due to the inhibition of double-stranded RNA-activated protein kinase (PKR) in these stranded RNA-activated protein kinase (PKR) in these cells. cells.

– In cells with Ras non-activated pathway, PKR In cells with Ras non-activated pathway, PKR autophosphorylates in the presence of viral transcripts, autophosphorylates in the presence of viral transcripts, which activates it and results in inhibition of viral protein which activates it and results in inhibition of viral protein synthesis, thus preventing viral replication. synthesis, thus preventing viral replication.

– In cells with activated RAS pathway the In cells with activated RAS pathway the autophosphorylation of PKR is inhibited keeping it in an autophosphorylation of PKR is inhibited keeping it in an inactive state and allowing viral replication and eventually inactive state and allowing viral replication and eventually oncolysis. oncolysis.

Reovirus in a cell with non-activated Ras pathway

Reovirus growth in a cell with Ras activated pathway

RATIONALERATIONALE

SarcomasSarcomas– Rare tumorsRare tumors– Very heterogeneousVery heterogeneous– Incurable when metastatic, median survival Incurable when metastatic, median survival

12 m.12 m.– Available treatments are few with low RR and Available treatments are few with low RR and

high toxicityhigh toxicity– There is an acute need for new drugs for There is an acute need for new drugs for

treatment of sarcoma treatment of sarcoma

RATIONALERATIONALE in vitroin vitro cytotoxicity assays in Ewing’s sarcoma, cytotoxicity assays in Ewing’s sarcoma,

rhabdomyosarcoma, synovial sarcoma, and rhabdomyosarcoma, synovial sarcoma, and osteosarcoma cell lines revealed complete cell kill. (Kolb osteosarcoma cell lines revealed complete cell kill. (Kolb et al.et al., AACR 2006) , AACR 2006)

in vivoin vivo antitumor effect seen in xenograft models of antitumor effect seen in xenograft models of pediatric sarcomas. (Ewing’s sarcoma and pediatric sarcomas. (Ewing’s sarcoma and rhabdomyosarcoma). rhabdomyosarcoma).

In all tumor lines evaluated, the reovirus exhibited In all tumor lines evaluated, the reovirus exhibited significant antitumor activity, including a complete significant antitumor activity, including a complete response in a rhabdomyosarcoma line.response in a rhabdomyosarcoma line.

CONCLUSIONCONCLUSION::

– REOLYSIN demonstrated excellent anti-tumor activity REOLYSIN demonstrated excellent anti-tumor activity in vitroin vitro and and in vivoin vivo in sarcoma cell lines. in sarcoma cell lines.

PHASE II multi-institutional, open-label, PHASE II multi-institutional, open-label, single agent study designed to characterize single agent study designed to characterize the efficacy and safety of REOLYSIN given the efficacy and safety of REOLYSIN given IV every 28 days in patients with bone and IV every 28 days in patients with bone and soft tissue sarcoma metastatic to lung.soft tissue sarcoma metastatic to lung.

OBJECTIVES

1. To measure tumor response and duration of response and describe any evidence of antitumor activity of intravenous multiple dose REOLYSIN in patients with bone and soft tissue sarcomas metastatic to the lung.

2. To evaluate safety of intravenous multiple dose of REOLYSIN

STUDY DESIGNSTUDY DESIGN

IV infusion over 60 minutes days 1-5IV infusion over 60 minutes days 1-5 REOLYSIN DOSE 3 X 10REOLYSIN DOSE 3 X 1010 10 TCIDTCID5050

Simon two-stage designSimon two-stage design– 38 patients will be accrued to the first stage38 patients will be accrued to the first stage– If 1 or more responses (prolonged SD If 1 or more responses (prolonged SD > 6 > 6

months, partial or complete response) up to months, partial or complete response) up to 52 patients will be accrued52 patients will be accrued

– The agent will be considered active if 3 or The agent will be considered active if 3 or more responses or prolonged SD are more responses or prolonged SD are observedobserved

INCLUSION CRITERIAINCLUSION CRITERIA Pts with bone or soft tissue sarcoma metastatic to the Pts with bone or soft tissue sarcoma metastatic to the

lung unresponsive to, or untreatable by, standard lung unresponsive to, or untreatable by, standard therapies (histologies include osteosarcoma, Ewing therapies (histologies include osteosarcoma, Ewing sarcoma family tumors, malignant fibrous histiocytoma, sarcoma family tumors, malignant fibrous histiocytoma, synovial sarcoma, fibrosarcoma, and leiomyosarcoma). synovial sarcoma, fibrosarcoma, and leiomyosarcoma).

The patients must have no sites of active disease other The patients must have no sites of active disease other than lungs unless agreed by the sponsor. than lungs unless agreed by the sponsor.

Have 2 or more measurable metastatic lesions in the Have 2 or more measurable metastatic lesions in the lungs detectable on CT scan. (RECIST)lungs detectable on CT scan. (RECIST)

At least 16 years of ageAt least 16 years of age Have no continuing adverse effects from prior therapies; Have no continuing adverse effects from prior therapies;

all such effects must have resolved to CTC AE version 3 all such effects must have resolved to CTC AE version 3 ≤ grade 1≤ grade 1

INCLUSION CRITERIAINCLUSION CRITERIA

Have received NO chemotherapy, radiotherapy, Have received NO chemotherapy, radiotherapy, immunotherapy, hormonotherapy or surgery within 28 immunotherapy, hormonotherapy or surgery within 28 days prior to receiving REOLYSINdays prior to receiving REOLYSIN

ECOG PS ECOG PS ≤ 2≤ 2 Life expectancy of at least 3 monthsLife expectancy of at least 3 months Laboratory results: Laboratory results:

– ANC ≥ 1.5 X 10ANC ≥ 1.5 X 1099

– Plats ≥ 100 X 10Plats ≥ 100 X 1099

– HB ≥ 9.0 g/dlHB ≥ 9.0 g/dl– Creatinine ≤ 1.5 X ULNCreatinine ≤ 1.5 X ULN– Bilirubin ≤ 1.5 X ULNBilirubin ≤ 1.5 X ULN– AST/ALT ≤ ULNAST/ALT ≤ ULN– Negative pregnancy test for females of childbearing potentialNegative pregnancy test for females of childbearing potential

EXCLUSION CRITERIAEXCLUSION CRITERIA Concurrent therapy with any other investigational Concurrent therapy with any other investigational

anticancer agent while on study. anticancer agent while on study. Have inadequate pulmonary function defined as a forced Have inadequate pulmonary function defined as a forced

expiratory volume in 1 second (FEV1) less than 50 % of expiratory volume in 1 second (FEV1) less than 50 % of predictedpredicted

Be on immunosuppressive therapy; have known HIV Be on immunosuppressive therapy; have known HIV infection or active hepatitis B or Cinfection or active hepatitis B or C

Be a pregnant or breast feeding womanBe a pregnant or breast feeding woman Have clinically significant pulmonary or cardiac disease Have clinically significant pulmonary or cardiac disease

including pre-existing arrhythmia, uncontrolled angina including pre-existing arrhythmia, uncontrolled angina pectoris, myocardial infarction 1 year prior to study entry, pectoris, myocardial infarction 1 year prior to study entry, or grade 2 or higher compromised LVEFor grade 2 or higher compromised LVEF

Dementia or altered mental statusDementia or altered mental status Any severe, acute or chronic medical or psychiatric Any severe, acute or chronic medical or psychiatric

condition condition

ENROLLMENTENROLLMENT

35 patients35 patients Tumor typesTumor types

– MFH 8 patientsMFH 8 patients– Synovial sarcoma 8 patientsSynovial sarcoma 8 patients– Osteosarcoma 6 patientsOsteosarcoma 6 patients– Leiomyosarcoma 6 patientsLeiomyosarcoma 6 patients– Undifferentiated round cell sarcoma 1 patientUndifferentiated round cell sarcoma 1 patient– Ewing sarcoma 1Ewing sarcoma 1– Liposarcoma 1Liposarcoma 1– Rhabdomyosarcoma 1 Rhabdomyosarcoma 1 – Chordoma 1Chordoma 1– High grade sarcoma 1High grade sarcoma 1– Alveolar sarcoma 1 Alveolar sarcoma 1

PATIENT CHARACTERISTICSPATIENT CHARACTERISTICS CharacteristicsCharacteristics

– 35 patients35 patients– Age 19-70 (median 51)Age 19-70 (median 51)– Sex Sex

• Female -16 patientsFemale -16 patients• Male -19 patientsMale -19 patients

– PS PS • 0 -12 patients0 -12 patients• 1 - 23 patients1 - 23 patients

PREVIOUS TREATMENTSPREVIOUS TREATMENTS Previous treatment lines for metastatic Previous treatment lines for metastatic

diseasedisease• More than 3 lines: 11 patientsMore than 3 lines: 11 patients• 1-3 lines: 20 patients1-3 lines: 20 patients• None: 4 patientsNone: 4 patients

Previous treatmentsPrevious treatments–Chemo only: 15 patientsChemo only: 15 patients–Chemo and XRT: 11 patientsChemo and XRT: 11 patients–None: 4 patients None: 4 patients –Biological agents: 5 patients (sorafenib, mTOR Biological agents: 5 patients (sorafenib, mTOR

inhibitors, bevacizumab) inhibitors, bevacizumab)

TOXICITIES TOXICITIES (based on 25 patients enrolled at IDD)(based on 25 patients enrolled at IDD)

Constitutional grade 1 (fever, chills, fatigue, myalgias): 22 patientsConstitutional grade 1 (fever, chills, fatigue, myalgias): 22 patients Respiratory grade 1 (cough, congestion): 14 patientsRespiratory grade 1 (cough, congestion): 14 patients Gastro-intestinal grade 1 (diarrhea): 10 patientsGastro-intestinal grade 1 (diarrhea): 10 patients Hematological: occurring during the week of treatment: Hematological: occurring during the week of treatment:

– Grade 2 ANC: 1 patient; Grade 3 ANC: 3 patients; grade 4 ANC-1 patient Grade 2 ANC: 1 patient; Grade 3 ANC: 3 patients; grade 4 ANC-1 patient (1 day- C2D3, C3D3).(1 day- C2D3, C3D3).

– Pt KS (received 16 cycles) grade 2-3 ANC during 13 cycles of treatment Pt KS (received 16 cycles) grade 2-3 ANC during 13 cycles of treatment (day 3-4). No neutropenia over the last 3 cycles. (day 3-4). No neutropenia over the last 3 cycles.

– Grade 2 thrombocytopenia – 2 patientsGrade 2 thrombocytopenia – 2 patients

– Grade 1 anemia- 3 patients. Grade 1 anemia- 3 patients.

Transaminitis: grade 2 AST/ALT – 1 patient (C1D8, C2D8, C3-5 D 5); Transaminitis: grade 2 AST/ALT – 1 patient (C1D8, C2D8, C3-5 D 5); grade 1 AST/ALT – 2 patients (C1D3 and C2D3)grade 1 AST/ALT – 2 patients (C1D3 and C2D3)

Palpitations: 2 patients (both with osteosarcoma, large lung mets). Palpitations: 2 patients (both with osteosarcoma, large lung mets).

1 patient had objective findings (arrythmia) received B blockers 1 patient had objective findings (arrythmia) received B blockers (etiology: possibly hypoxia).(etiology: possibly hypoxia).

EFFICACYEFFICACY 1 patient (synovial sarcoma) SD after cycle 16 (ongoing). 1 patient (synovial sarcoma) SD after cycle 16 (ongoing). 1 patient Ewing sarcoma SD after 8 cycles (ongoing). 1 patient Ewing sarcoma SD after 8 cycles (ongoing). 1 patient with osteosarcoma SD after 6 cycles (ongoing).1 patient with osteosarcoma SD after 6 cycles (ongoing). 3 other patients SD after 4 cycles (leiomyosarcoma, 3 other patients SD after 4 cycles (leiomyosarcoma,

chordoma, MFH).chordoma, MFH). 15 patients SD after 2 cycles. 15 patients SD after 2 cycles. 15 patients PD.15 patients PD. No tumor reduction.No tumor reduction. 6/29 patients had SD > 16 weeks 6/29 patients had SD > 16 weeks 21%21% 15/29 patients had SD for at least 8 weeks (2-16 15/29 patients had SD for at least 8 weeks (2-16

months) months) 52%52% 4 patients are too early for evaluation; 2 patients came 4 patients are too early for evaluation; 2 patients came

off study before tumor evaluation.off study before tumor evaluation.

Completed Cycles Per Patient

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Patient 0101Patient 0102Patient 0103Patient 0104Patient 0105Patient 0106Patient 0107Patient 0108Patient 0109Patient 0110Patient 0111Patient 0112Patient 0113Patient 0114Patient 0115Patient 0116Patient 0117Patient 0118Patient 0119Patient 0120Patinet 0121Patient 0122Patient 0123Patient 0124Patient 0125Patient 0126Patient 0127Patient 0128Patient 0129Patient 0130Patient 0131Patient 0132Patient 0133Patient 0134Patient 0135Patient 0136

Pati

en

t ID

Number of Cycles

CONCLUSIONCONCLUSION REOLYSIN PHASE II SARCOMAREOLYSIN PHASE II SARCOMA

– 35 patients enrolled to date35 patients enrolled to date– Mild to moderate toxicitiesMild to moderate toxicities– 22ndnd cycle better tolerated than 1st cycle better tolerated than 1st– 3 patients SD for at least 6 months 3 patients SD for at least 6 months – 21% patients SD >16 weeks21% patients SD >16 weeks– 52% patients SD for at least 8 weeks52% patients SD for at least 8 weeks

CONCLUSIONCONCLUSION

The study achieved the established The study achieved the established objectives after the first 33 patients enrolledobjectives after the first 33 patients enrolled

Enrollment will continue to 52 patients Enrollment will continue to 52 patients Future studies with Reolysin in combination Future studies with Reolysin in combination

with chemotherapy are planned in this with chemotherapy are planned in this patient populationpatient population

Acknowledgements

IDD at CTRC/UTHSCSA: Tony Carmona, Alain Mita, John Sarantopoulos, Kamalesh Sankhala, Francis GilesMontefiore Medical Center: Sanjay GoelMayo Clinic: Scott OkunoU Michigan Cancer Center: Rashmi Chugh Oncolytics: Karl Mettinger, Matt Coffey, Brad Thompson, Merle Kirkpatrick, Cathy Ward.

THANK YOU

              The Institute for Drug Development

A leader in anticancer drug development