Clinical Trials? John Buscombe

Clinical Trials? John Buscombe

Introduc7on Look at the role of clinical trials in radionuclide therapy Understand some of the terms used in clinical trials Look at two recent examples Commercial trial Alphadren Academic trial - HiLo

Why clinical trials Provides evidence base for clinical prac7ce Provides data for toxicity and efficacy which is required for consent Provides evidence for re- imbursement Enables nuclear medicine to compete with other treatment modali7es

What is needed for success Who is this

What is needed for success

What team for clinical trials NM doc Oncologist Study nurse Physicist NM techs Sponsor Clinical trials cordinator

ECTD Most studies in Europe has to follow ECTD Defines roles and responsibili7es Provides a quality mark for all involved Ensures any medicinal product complies with GMP Will allow studies done in different countries to have comparable results

GMP Good manufacturing prac7ce Ensures quality of products used in trials Each component must come from a GMP source Any product must be made to GMP with all records kept of what was used and how it was put together

The protocol This is the method that must be completed by all those undertaking trial Defines inclusion and exclusion criteria Defines what treatments to be given and when Defines what tests will be done to iden7fy efficacy and toxicity Type of protocol defined by stage of trial

How do we define response Radiological response RECIST Defines Par7al response (a drop of >50% in tumour volume Complete response no tumour ley Disease progression (an increase of >50% in tumour volume Disease stability all other responses

Limita7on Radiological response limited use in some tumours such as lymphoma May not reflect survival Be[er parameters look at survival Overall survival Progression free survival Time to treatment failure Normally look at median eg in a study of 100 people the median OS in when the 50 th pa7ent dies Other measures such as biochemistry

Types of trials Pre- clinical will be needed for new agents Phase- 1 Defines maximum tolerated dose and for radio- isotopes dosimetry. In oncology normally done on pa7ents with advanced cancers up to 25 pa7ents Phase- 2. Tries to define efficacy limited number of centres with fixed ac7vity or fixed dose can be up to 100 pa7ents

Phase I Dose Escala7on Schedule No of Patients Treatment Dose increase 3 10 mg CHT-25 + 370 MBq/ m 2 131 I 3 10 mg CHT-25 + 740 MBq/ m 2 131 I 3 * 10 mg CHT-25 + 1480 MBq/m 2 131 I 3 * 10 mg CHT-25 + 2220 MBq/m 2 131 I 3 * 10 mg CHT-25 + 2960 MBq/m 2 131 I X 2 X 2 X 1.5 X 1.3 * Bone Marrow Harves7ng required

Patient Gender Age Histology Previous therapy 1* Female 34 ALCL Hodgkin s like lymphoma 2 Female 70 High Grade B cell NHL CHLVPP/ PABLOE, CHOP,BEAM + PBSCT, RT to right SCF CHOP + IT MTX, RT to right axilla and neck 3* Male 36 Hodgkin s disease PABLOE, CHLVPP/ PABLOE, EPIC, BEAM + PBSCT 4* Male 34 Hodgkin s disease ABVD, LOPP/ EVAP, IVE, BEAM + PBSCT, RT to mediastinum 5* Male 62 Peripheral T Cell lymphoma CHOP, IVE, Cyclophosphamide, Beam + PBSCT 6* Male 33 Hodgkin s disease ABVD, CMOPP, CHLVPP, Splenectomy, IVE, mini BEAM + PBSCT 7* Male 42 Hodgkin s disease ABVD, CHLVPP, BEAM + PBSCT, Stamford V, Chlorambucil, Gemcitabine, Lomustine 8 Male 62 HTLV associated adult T-cell lymphoma CHOP + IT MTX, High dose MTX 9 Male 27 Hodgkin s disease ABVD, ESHAP, mini BEAM, mediastinal RT * Previous high dose procedure

Administered ac-vity in MBq/m 2 (actual administered ac-vity) Patient #1 #2 #3 #4 Cumulative activity 1 370 (663) 370 (663) 2 370 (573) 370 (573) 3 370 (725) 740 (1377) 1110 (2102) 4 740 (1380) 1480 (1868) 2220 (3395) 370 (554) 4810 (7197) 5 740 (1286) 1480 (2220) 2220 (3506) 6 740 (1104) 740 (1104) 7 1480 (2397) 2220 (2560) 2960 (4553) 6660 (10507) 8 740 (1093) 740 (1093) 9 740 (1105) 1480 (2104) 2220 (3239) 4440 (6448) Repeated therapy possible at 1 month if localisa7on > 3% injected ac7vity/kg + no stem cell rescue required

Incidence and CTC grade of haematological toxicity in rela7on to administered ac7vity Administered activity (MBq per m 2 ) Treatment no. Haemoglobin Neutrophils Lymphocytes Platelets 370 4 G1(1),G2(2) G3(1) G1(1),G2(1) G3(2) G2(1) G3(1) 740 6 G1(1),G2(5) G2(1) G3(4) G1(1) G2(1) 1480 4 G1(1),G2(2) G1(2),G2(3) G3(4) G2(1), G3(3) G3(2) G4(1) 2220 3 G2(2), G4(1) G2(1), G3(1) G3(3),G4(1) G3(1) G4(2) 2960* 1 G2 G4 G3 G3 *DLT with toxic death due to pneumocys*s pneumonia

SPECT image revealing tumour localisa7on of 131 I- CHT25 in pa7ent 07 LeY axillary Lymph node Right rib deposit Tumour localisa7on at > 3% injected ac7vity seen in 12/18 therapies

Patient no. Dose Level (MBq/m 2 ) FDG-PET CT (WHO criteria) Comment 1 370 - - Clinical progression 2 370 - PD 3 370 PR SD 740 - SD Clinical progression 4 740 PR SD 1480 CR SD 2220 CR SD 370 PR SD 5 740 PR PR 1480 PR CR 6 740 SD SD 7 1480 - SD 2220 PR PR 2960 - - Not available for scanning 8 740 - PD Scanned at referring Hospital 9 740 SD SD 1480 SD SD 2220 PD PD Partial PET response at 1 month

FDG- PET Response in Hodgkin s disease following 554 MBq (pa7ent 04) Medias7nal Lymphadenopathy

Krenning et al JCO 2005

Lu- 177 octreotate (n=310) Kwekkeboom JCO 2008 Carcinoid n=188 1% CR, 22% PR, 17% MR, 42% SD, 20%DP PET non func n=72 6% CR, 36% PR, 18%MR, 26% SD, 14% DP PET func n=19 0% CR 60% PR, 20% MR, 30% DS, 10% PD

Survival post Lu- 177 oct n=310

Use of Bexxar as 1 st line Tx Clinical trials used pa7ents who have failed many therapies How would Bexxar do as first line therapy Vose et al NEJM 2005 Treated 76 pa7ents with first line therapy Bexxar alone was used with no comparison (BEAM alone about 15-25% CR)

Survival rates all pa7ents Vose et al NEJNM 2005

Type of trials Phase 3. Randomised control trial of treatment being tested against placebo or other standard treatment(s) Needs 200 to 1000 pa7ents Many centres Needed for drug registra7on Phase 4. Post market surveillance Really a marke7ng method

What is Zevalin? Ibritumomab An7- CD20 murine parent of rituximab Tiuxetan Chelator, conjugated to an7body forming strong urea- type bond to 90 Y Y[rium- 90 t 1/2 = 64 hours, Beta emission - 5mm

Representative patient: 111 In-labelled Zevalin imaging Abdominal SPECT 4 hours 66 hours 139 hours Abdominal CT

Does it work?-results of US trials (73 patients had Zevalin & 70 had Rituximab alone) Patients (%) 100 90 80 70 60 50 40 30 20 10 0 OR OR CR CR 90 Y Zevalin Rituximab 80 p = 0.002 56 30 p = 0.04 16 90 Y Zevalin Rituximab International Workshop NHL Response Criteria Witzig TE, et al. Blood 2000; 96: 831a

Time to progression Progression free (%) 100 80 60 40 All patients Complete responders p = 0.144 90 Y Zevalin (n = 73) Rituximab (n = 70) 20 p = 0.173 0 0 6 12 18 24 30 36 Months Witzig TE, et al. Blood 2000; 96: 831a

Performing a RCT Pa7ents need to consent before randomisa7on Pa7ents can withdraw consent but this should be discouraged All results must be recorded into the CRF Principal inves7gator at each responsible that the trial is properly conducted

A commercial trail For 50 years radioisotopes have been used to treat pain from bone metastases Many authors have felt that pa7ents treated with radioisotopes lived longer than expected but this has never been demonstrated in an RCT Could giving a radioisotope improve survival and is so which on

Development of radionuclide therapy Early work with P- 32 for bone pain Efficacy good and low cost but increased toxicity (?) especially to bone marrow has limited its use Sr- 89, first true bone seeking agent, also has significant toxicity in widespread mets

Pure beta emi[ers Isotope T1/2 Beta energy comments P32 14.3d 1.71 Low TBR = 2 at most Sr-89 50.5 1.46 Fixed dose 150 MBq

Metastron Well tolerated Up to 80% pa7ent will have fall in Pts of >50% at week 6, recovery normal G3 and G4 toxicity rare Some pallia7on in 70% of pa7ents Complete pain relief in 22% (Laing et al) Repeat therapy at 6 months

What agent to use in this pa7ent (62M pain in many sites, HB 10, Pts 150) Do we wish to use an isotope with long half life which may con7nue to irradiate the bone marrow for up to 2 months??

Gamma emi[ers Isotope T ½ Beta energy Sm-153 EDTMP 1.93d 0.81 MeV 103 Gamma emission Re-186 HEDP Sn-117m DTPA 3.7 1.07 MeV 137 14 EC only 158

Gamma emi[ers Most experience with Samarium- 153 ethyldiaminetetrametylenephosphonate Generally shorter T1/2 than beta emi[ers Not dependent on calcium deposi7on TBR oyen 10:1 or higher Faster onset and clearance

24 hours post 2.3GBq Sm- 153 Images not so clear as low energy reduces count rate. Note at 24 hours no renal or bladder ac7vity seen but this is not a superscan

Sm- 153 EDTMP (lexidronam) Results of US/ European MCT for Merrill Pharm Phase III trail in prostate cancer Randomised to placebo lexidronam or Sm- 153 product

Sm- 153 EDTMP Effect on Pts and WBC Related to radioac7vity not lexidronam Recovered by 6 weeks

Conclusions RCTs are base of research in clinical medicine Logical progression Phase 1 Phase 2 Phase 3 Needed for acceptance by oncology etc