Overview of Lymphoma Clinical Trials

Beatson West of Scotland Cancer CentreUKONS Conference November 2018

Dr Pam McKay

Clinical trials

Treatment related

• New treatment

• does it work?

• how does it work?

• is it better than standard treatment?

• Existing treatments

• comparing one treatment with another

• comparing different ways of using treatment e.g. doses, scheduling

Medical research involving human participants

• Pathology e.g. molecular subtypes – MAPLE study

• Radiology e.g. use of PET/CT scans to guide treatment – PETREA study

• Patient pathway - Horizons study

• Late effects e.g. fertility – RATHL ovarian sub-study

Clinical Trials

• Phase 1 – small trials; often aim to find best dose or test safety

• Phase 2 – aim to find out more about the safety and effectiveness of the treatment

• Phase 3 – larger trials; test a new treatment or a new way of using a treatment against the standard treatment

• Phase 4 – to find out more about a drug after it has been licensed

Advantages Potential disadvantages

• Access to latest treatments

• Access to information

• Access to expert staff

• Careful follow up

• Longer follow up

• Helping others in future

• Uncertainty about outcome • Might be in group with worse outcome

• Unexpected side effects

• Greatest in phase 1 trials (usually for patients with no other treatment options)

• Extra hospital visits

• Reassuring or stressful?

• Extra tests

Subtypes

• Hodgkin’s lymphoma

• Diffuse Large B cell lymphoma

• Follicular lymphoma

Hodgkin’s Lymphoma

• ABVD – standard treatment for many years (70-80% cure rates)

• Evens et al, 2007 - importance of delivering full doses on time

• Early stage disease – ABVD 2-4 cycles + radiotherapy

• Can radiotherapy be omitted in patients with early stage HL who are PET negative after 3 cycles ABVD? RAPID study

• Advanced stage disease – ABVD x 6

• Can bleomycin be removed from ABVD if PET negative after 2 cycles of ABVD? RATHL study

• Does substitution of Brentuximab for Bleomycin improve results? ECHELON study

• Can we reduce toxicity of intensive escBEACOPP regimen by giving less cycles if PET negative after 2 cycles? HD18 study

RAPID study – randomization between no further treatment and radiotherapy in patients who are PET negative after 3 cycles of ABVD

Radford et al, 2015. NEJM, 372; 1598-1607

RAPID study

• 3-year progression-free survival rate was 97.1% in the radiotherapy group and 90.8% in the group with no further therapy

• Modest improvement in the 3-year PFS rate (6.3%) can be obtained with the addition of radiotherapy

• Avoidance of RT may reduce incidence of second cancers and cardiac disease

2 cycles ABVD

PET positive

PET 1

4 cycles BEACOPP-14or 3 cycles escBEACOPP

RATHL1200 advanced HL

RT or salvage 2 cycles BEACOPP-14or 1 cycle escBEACOPP

PET positive PET negative

Endpoint : PFS

4 cycles ABVD

PET negativeRandomize

No further treatment

No RT

4 cycles AVD

no bleomycin

PET 2

PET 3

Johnson et al, 2016. NEJM, 374: 2419-2429

RATHL study

• ~1200 patients; UK, Europe, Australia, NZ

• 83.7% of patients had a negative PET2

• 3 yr PFS 85.7% (ABVD) vs 84.4% (AVD)

• 3 yr OS 97.2% vs 97.6%

• Improved PFS in patients escalated to BEACOPP c.f. historical controls

Conclusion:

• Bleomycin can be omitted from C3-6 with no loss of efficacy

• Respiratory events reduced

• Escalation to BEACOPP in PET + patients à improved PFS

Primary Endpoint: PFS for PET-negative randomized, eligible patients

(Median follow up 41 months)

Intention to treat analysis: Per protocol analysis:

HR: 1.13 (0.81 – 1.57), p = 0.483 Year PFS, ABVD: 85.7% (95% CI: 82.1 – 88.6)

3 Year PFS, AVD: 84.4% (95% CI: 80.7 - 87.5)

HR: 1.10 (0.79 – 1.53), p = 0.583 Year PFS, ABVD: 85.3% (95% CI: 81.6 – 88.4)

3 Year PFS, AVD: 84.6% (95% CI: 80.8 - 87.7)

ABVD-AVD = 1.6% (-3.2 - +5.3) ABVD-AVD = 1.3% (-3.7 - +5.1)

Overall survival: PET-2 negative patients

3 year OS ABVD: 97.2% (95.1 – 98.4) AVD: 97.6% (95.6 – 98.7)

Echelon I study:ABVD v A-AVD

• Phase III, commercial study

• Untreated HL, stage III-IV

• ABVD v A(brentuximab)-AVD x 6

• 2 year modified PFS: 77.2% vs 82.1%

• A-AVD – superior efficacy (4.9% improvement in modified PFS)

• Peripheral neuropathy more common with A-AVD (67% vs 43%)

• Serious pulmonary toxicity more common with ABVD (3% vs 1%)

Connors et al, 2018. NEJM, 378; 331-344

Modified PFS per independent review

TimeA+AVD

(95% CI)ABVD

(95% CI)2-year 82.1

(78.7–85.0)77.2

(73.7–80.4)

Median follow-up (range): 24.9 months (0.0–49.3)

CategoryA+AVDN=117

ABVDN=146

Progression 90 102

Death 18 22

Modified progressionChemotherapyRadiotherapy

972

22157

1.0

0.8

0.6

0.4

0.2

0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52

664670

640644

623626

606613

544522

530496

516476

496459

474439

447415

350328

334308

311294

200179

187168

174153

9978

8568

7762

2716

2413

2112

61

41

41

00

00

Time from randomization (months)

Prob

abili

ty o

f mod

ified

PFS

No. of patients at risk:A+AVDABVD

HR 0.77 (95% CI: 0.60–0.98)Log-rank test p-value: 0.035

A+AVDABVD

0.9

0.7

0.5

0.3

0.1

Number of events

Connors, J. et al: Abstract no 0006, ASH 2017

Peripheral neuropathy and pulmonary events

• *Includes the preferred terms peripheral sensory neuropathy, PN, hypoesthesia, polyneuropathy, paraesthesia, muscular weakness, peripheral motor neuropathy, peroneal nerve palsy, muscle atrophy, hypotonia, autonomic neuropathy, neuralgia, burning sensation, dysesthesia, gait disturbance, toxic neuropathy, neurotoxicity, and sensory disturbance; PN, peripheral neuropathy

• †Includes the preferred terms lung infiltration, pneumonitis, interstitial lung disease, acute respiratory distress syndrome, organizing pneumonia, pulmonary fibrosis, and pulmonary toxicity

67%

43%

• Drug discontinuations due to PN:– A+AVD 7%– ABVD2%

0%

20%

40%

60%

80%

A+AVD ABVD

Patie

nts (

%)

Treatment-emergent PN*

Grade 3-4Grade 2Grade 1

2%

7%

<1%

3%

0123456789

10

Category 1 Category 2 Category 3 Category 4

A+AVD ABVD

All

A+AVD ABVD

Grade ≥3

Interstitial lung disease†

Patie

nts (

%)

Connors, J. et al: Abstract no 0006, ASH 2017

Early interim PET within the German HD18 study

Borchmann P. et al: ASH 2017 Abstract 0737

Advanced stage Hodgkin

lymphoma

PET2 +ve (DS3-5)

PET2 –ve (DS1-2)

eBEACOPP x2

eBEACOPP x4/6

R-eBEACOPP x 4/6*

eBEACOPP x 4/6

Borchmann et al, 2017, Lancet. 390; 2790-2802

HD15 Lancet. 2012 May 12;379(9828) 1791-9: 6 cycles more effective and less toxic than 8 (* amendment, 2011 – standard

treatment 6 cycles in total)

eBEACOPP x2

R

R

PFS and OS for iPET2 negative patients

5 year PFS 92%

5 year OS 97.8%

Non-inferiority using 4 cycles and less infectionsNo TRM2.7% secondary neoplasm

Borchmann et al, 2017, Lancet. 390; 2790-2802

PFS and OS for iPET2 positive patients

Rituximb : no benefit

5 year PFS 88%

5 year OS 94%

Borchmann et al, 2017, Lancet. 390; 2790-2802

German HD18 study - Conclusions

4 cycles eBEACOPP is standard of care if PET negative after 2 cycles

Rituximab is of no additional benefit

Current treatment of HL patients at Beatson

Early stage

• 2-4 cycles of ABVD depending on risk factors followed by radiotherapy

• Discuss RAPID trial on an individual basis, especially young females

Advanced stage

• Majority managed by RATHL approach ie ABVD x 6 with omission of bleomycin if PET scan negative after 2 cycles

• Consider escBEACOPP as per HD18 if high prognostic score, especially in males

• EscBEACOPDac may reduce infertility

Elderly HL - PFS with multi-agent chemotherapy

Age >70Cannot perform ADLs

Andrew M. Evens et al. Blood 2012;119:692-695 ©2012 by American Society of Hematology

BREVITY study

• Untreated HL

• Not for standard treatment due to age, frailty, co-morbidities

• Single agent brentuximab, 3 weekly

• 4 cycles then evaluate by PET/CT

• If CR à further 8 (total 12)

• If PR à further 4 then if CR, further 8 (total 16)

• ORR 84% (CMR or PMR at PET 4)

(N=26/31)

• CMR rate at PET4 was 26%

(N=8/31)

Median PFS 7.4 months

PFS for patients in CMR 11.9 months

Gibb et al, ICML 2017.

Progression-Free Survival

• Tolerable therapy but high incidence of low-grade toxicity and dose reductions in this difficult-to-treat population

• Peripheral neuropathy an issue• High overall response rates but

mainly partial response

• PFS unsatisfactory

The impact of treatment type and age on ovarian toxicity in the rathl study

RA Anderson, R Remedios, AA Kirkwood, P Patrick, L Stevens, T Roberts, AM Carella, M Federico, A Fossa, C Hatton, N Kalakonda, DW Milligan, P McKay, J Radford, C Rowntree, F Scott, P Smith,

PWM Johnson

MRC Centre for Reproductive Health, The University of Edinburgh

Cancer Research UK & UCL Cancer Trials Centre University College London

Cancer Research UK Centre, Southampton, UK.

Premature Ovarian Insufficiency following treatment is an important morbidity for patients treated for Hodgkin’s lymphoma

• Many patients present in their second or third decade

• Methods for preservation of female fertility are generally complex or unproven

• Prediction of ovarian failure at present is done by age

• AMH is a protein hormone produced by small growing follicles in the ovary

• AMH level reflects the number of primordial follicles, the ‘Ovarian Reserve’, which determines reproductive lifespan

• Could measurement of anti-Mullerian hormone (AMH) be informative?

Sequential changes in AMH

BEACOPP

ABVD/AVD

0

0.5

1

1.5

2

2.5

Baseline EOT at 1 year

AB(V)DBEACOPP

Risk of premature ovarian insufficiency (POI)(defined as FSH > 25 iu/l)

ABVD/AVD BEACOPP pWomen 35 or over, N (%)

End of treatment2 years

37 (66)4 (10)

11 (100)7 (70)

0.022*<0.001**

Women under 35, N (%)End of treatment2 years

21 (14)0

16 (89)2 (20)

<0.001*0.007**

Median time to recovery (days)35 or overUnder 35

516209

824664

0.008***<0.001***

% Recovery at 2 yearsK-M estimate (95% CI)

35 or overUnder 35

78% (68 -86)93% (89-96)

37% (19 -65)56% (36 -77)

* Chi squared test, ** Fisher’s exact test, *** Log rank test.

Time to recovery of FSH below 25 iu/l

Can pre-treatment AMH be used to predict the risk of premature ovarian failure?

FSH>25 after 1 yearFSH>10 after 1 year

P=0.03 P=0.12

No Yes No Yes

Conclusions

• BEACOPP regimens are significantly more toxic to ovarian function than ABVD, an effect which worsens with age

• There is no detectable evidence of lasting ovarian damage by ABVD in patients under 35

• Reduction in AMH levels appears to be permanent following BEACOPP, although a minority of women will recover normal gonadotrophin levels

• Pre-treatment AMH may be a means to identify those at highest risk of POI following chemotherapy, but this requires further study with a larger cohort of patients.

Anderson et al, 2018. Lancet Oncology, 19; 1328-1337

Diffuse Large B cell lymphoma (DLBCL)

• Commonest subtype of lymphoma

• Aggressive but curable

• 1994: 7-8 drug regimens no better than CHOP but

significantly greater toxicity à CHOP is standard of care

• 2002: addition of rituximab to CHOP (R-CHOP) àimprovement in response rates, progression free

survival and overall survival by ~15% à RCHOP21 = standard of care

How can we improve on R-CHOP21 ?

• Chemotherapy scheduling

• 6 vs 8 cycles RICOVER-60 study

• 14 vs 21 day cycles CRUK study

• Different monoclonal Ab

• ofatumumab, obinotuzumab Goya study

• Additional agents

• bortezomib REMODL-B study

• ibrutinib PHOENIX study

• Addition of radiotherapy RICOVER-60 study

• Infusional chemotherapy DA–EPOCH - R

Chemotherapy scheduling

• Established that 8 cycles R-CHOP no better than 6 cycles

• RICOVER-60 study1

• R-CHOP14 day cycle no better than 21 day cycle

Pfreundschuh et al, 2008. Lancet Oncol, 9(2); 105-116 Cunningham et al, 2013. Lancet, 381: 1817-1826

Different monoclonal antibody

Goya study – 1418 patients

• CHOP + Obinutuzumab (G-CHOP) vs R- CHOP

• Obinutuzumab –anti CD20 antibody, more potent than R

• No difference in response rate, PFS or OS

• More significant toxicity with G-CHOP.

PFS

OS

Vitolou et al, 2017. J Clin Oncol, 35(31): 3529-3537

Additional agents

ABC DLBCL – poorer prognosis à focus of attention

Some novel agents appear to have preferential activity in ABC type

Bortezomib, ibrutinib, lenalidomide – in combination with R-CHOP

Additional agent

REMODEL-B study

• Large phase III study, multicentre, UK• 1132 patients from 109 sites• First line treatment of DLBCL• R-CHOP vs R-CHOP + Bortezomib• No difference in outcome

Phoenix study

• Large phase III study• R-CHOP vs R-CHOP + Ibrutinib• Ibrutinib - BTK inhibitor• Preferential activity in ABC type DLBCL• follow up ongoing

Addition of Radiotherapy

German RICOVER-60 trial

• Patients aged >60 yrs

• 6xR-CHOP14 + 2xRituximab

• Value of adding radiotherapy to sites of initial bulk (>7.5cm) or extranodal disease

• CONRAD study

R-CHOP vs DA-EPOCH-R in DLBCL

Wilson et al, ASH 2016, #469

• Phase II study, haematologica, 2012: 81% PFS at 4 yrs with DA-EPOCH-R

• Phase III, randomised study vs R-CHOP (SOC)

• 524 pts

• Analysis by age (<60 vs ≥60) and GCB vs ABC in process

• Preliminary analysis (all patients): no difference in EFS or OS, median FU 4.9 yrs

• DA-EPOCH-R more toxic

• Discontinuation due to ae’s: 5.6 vs 1.7%

• Grade 4 neutropenia: 90 vs 56%

• Grade 4 thrombocytopenia: 35 vs 6.1%

• Grade 3 or 4 FEN: 37 vs 19%

• Grade 3 neuropathy

• Motor : 8 vs 1%• Sensory: 15 vs 3%

Management of patients with poor cardiac function/multiple co-morbidities

• INCA study

• Multicentre, randomised, phase II trial

• 1st line DLBCL

• Not suitable for anthracycline due to cardiac or other co-morbidities

• IO-R-CVP v Gem-R-CVP

• IO= inotuzumab ozogamacin – anti CD22 conjugated to calicheamicin

(potent anti tumour antibiotic)

• 6 cycles, 3 weekly intervals

• 1y end point - PFS

Current management of DLBCL at Beatson• R-CHOP x 6 • R-CODOX-M/IVAC – double hit lymphomas• Consider RT if PET +ve lesion on EOT scan

Molecular Profiling Studies - MaPLe

• DLBCL– newly diagnosed

• Samples à molecular diagnostic lab, HMDS

• Molecular profiling

• Basic clinical data collected

• In event of progression, patient screened for targeted treatment • EZH2 mutation present à Epizyme study

Anthracycline cardiomyopathy: detection and prevention in high-risk cancer patients

Cardiac CARE Study A multicentre prospective randomised open-label blinded end-point controlled trial of high-sensitivity cardiac

troponin I-guided combination angiotensin receptor blockade and beta blocker therapy to prevent cardiac toxicity in breast cancer and lymphoma patients receiving anthracycline adjuvant therapy.

Baseline cardiac MRI

Patient is approached and agrees to participate, attends screening visit and consents to study

Anthracycline treatment cycles

Anthracycline treatment completed

Post-anthracycline cardiac MRI

Patient attends clinic for diagnosis & explanation of treatment

candesartan + carvedilol

Titration clinics

Maximum tolerated doses of candesartan + carvedilol*

Drug treatment continues until final MRI scan

Standard care

1:1 Randomisation

Radiotherapy(for some patients)

cTnI concentrations at 2, 4 and 6 months

Pre-cycle 2 cTnI ≥ 6ng/L

Pre-cycle 6 cTnI ≥ 23ng/L

1 m

onth

6 m

onth

s3,

4 o

r 6 c

ycle

s(6

, 9 o

r 15

wee

ks)

cTnI concentrations recorded prior to each cycle

9-20

day

s

* Target doses: Candesartan 32 mg o.d.Carvedilol 25 mg b.d.

Extranodal Lymphomas

Primary Mediastinal B cell lymphoma

IELSG 37 study

• Ph III, multicentre

• 1st line treatment

• Standard of care is R – chemotherapy followed by radiotherapy (RT)

• Can we use PET scan to determine need for RT?

• If PET negative à randomize between RT or no further treatment

Secondary CNS Lymphoma

MARIETTA study

• Systemic B-cell lymphoma with CNS involvement at diagnosis or at relapse

• Outlook very poor

• Sequential MATRIX and R-ICE, followed by high-dose chemotherapy + ASCT

Relapsed DLBCL

Epizyme study

• Phase II study, multicentre

• > 2 previous lines of therapy

• Tazemetostat (EZH2 histone methyl transferase inhibitor)

• Single agent, oral therapy

• Well tolerated

ARGO study

• Phase II study, multicentre

• Patients who have relapsed post ASCT or unsuitable for transplant

• R + gemcitabine + oxaloplatin (RGO) vs

RGO + atezolizumab

(check point inhibitor)

Follicular lymphoma (FL)

Commonest low grade lymphoma, incurable

Treatment not always required at diagnosis

• “Watch and wait”

Watch & wait vs rituximab study

• Rituximab à delay in time to require definitive treatment compared to

observation alone

• Potential toxicity from infection

Addition of rituximab to chemotherapy à improved outcomes – response rates, PFS, OS

Rituximab maintenance (2 monthly for 2 years) improves PFS but not OS (PRIMA study)

Ardeshna et al, 2014. Lancet Oncol, 15(4); 424-435.

PRIMA update

©2013 by American Society of HematologySalles, G et al, Blood 2013, 122, 509.

PFS42.7%

PFS 59.2%

6 yrNo overall survival benefit

Standard of care:Rituximab + chemotherapy eg CVP, CHOP, bendamustineMaintenance Rituximab for 2 yearsCurrent q’s:

1) Can other CD20 antibodies eg obinutuzumab result in better outcome? GALLIUM study

2) Can PET/CT scans be used to determine those patients who will not benefit from maintenance rituximab? PETREA study

PRIMA study

GALLIUM study• Large phase III study

• >1200 patients

• Comparison of obinutuzumab (O) + chemo versus rituximab (R) + chemo

• chemo - CHOP or CVP or bendamustine

• maintenance O or R for 2 years

• 3yr PFS 80% for O-chemo vs 73.3% for R-chemo

• Adverse events (gd3-5) more frequent with O (74.6 vs 67.8%)

• Non-lymphoma related mortality higher in bendamustine treated patients (5%) vs CHOP and CVP (<2%)

• Mainly infection– marked reduction in CD4 helper cells – persists up to 18 months

Marcus et al, 2017. NEJM; 377: 1331-1344

GALLIUM study – reduction in risk of PFS event

Obinutuzumab + chemo approved by NICE but not SMC for 1st line treatment

PETREA study

• R-chemotherapy (CVP, CHOP or bendamustine)

• PET/CT scan at diagnosis and post chemotherapy

• If PET/CT negative after R-chemo, randomize between maintenance R (MR) and observation

• If PET/CT positive after R-chemo, randomize between MR and MR + lenalidomide

Relapsed FL - GADOLIN Study

ph 3 study, ~ 400 pts with indolent NHL (80% FL)rituximab refractory

Sehn et al. Lancet Oncol 2016;17(8):1081-1093.

GADOLIN updateAdditional 10mths FU

• Median PFS 25.8 (G-B) v 14.1 mths

• Median OS not reached (G-B) v 53.9 mths

• 43% reduction in risk of PD or death with G-B

• No new safety signals

• Severe neutropenia & infusion related reactions more common with G-B

Cheson et al, 2018. J Clin Oncol; 36 (22): 2259-2266

SMC approved

Other FL relapse studies

• Idelalisib▼ in double-refractory FL, 101-09 study1,2

• refractory to both rituximab and an alkylating agent*

• median of 4 prior therapies1,2

• 56% ORR (14% CR); med PFS 11 months (in FL cohort; n=72)2

• SMC-approved

• toxicities• REBEL study – rituximab and lenalidomide +/- bendamustine• Epizyme study – tazemetostat – multiple relapsed FL à very encouraging

results especially if have EZH2 mutation (~70% RR)

1. Gopal et al, 2014. NEJM; 370 (11): 1008-1018; 2. Salles et al. Haematologica, 2017 Apr; 102(4): e156–e159

*Idelalisib is licensed in Europe as monotherapy for the treatment of adult patients with follicular lymphoma (FL) that is refractory to two prior lines of treatment

Conclusion

• Clinical trials are important in improving medical care for ALL patients

• They may improve outcome for the individual patient

• They may provide treatment opportunities when standard treatment has been exhausted