Overview of Lymphoma Clinical Trials

Dr Pam McKay

Beatson West of Scotland Cancer CentreLymphoma Action Patient Conference

September 2018

Clinical trials

medical research involving human participants

• 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 eg doses, scheduling

Clinical trials

• pathology eg molecular subtypes – MAPLE study

• radiology eg use of PET/CT scans to guide treatment

• patient pathway eg Horizons study

• late effects eg fertility – RATHL ovarian substudy

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 – after a drug has been licensed, to find out more about it

Potential Advantages

• access to latest treatments

• access to information

• access to expert staff

• careful follow up

• longer follow up

• helping others in future

Potential Disadvantages

• 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

Diffuse Large B Cell Lymphoma

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

• 2002: addition of rituximab to CHOP (R-CHOP) improvement in response rates, progression free survival and overall survival by ~15%

• RCHOP21 =standard of care

R-CHOP vs CHOP

1. Coiffier et al. Blood, 2010.

How can we improve on R-CHOP21 ?

• chemotherapy scheduling

• different monoclonal Ab

– ofatumumab, obinotuzumab

• additional agents

– bortezomib, ibrutinib

• addition of radiotherapy

Chemotherapy scheduling

– established that 8 cycles R-CHOP no better than 6 cycles

– 14 day cycle no better than 21 days

PFS

OS

Different monoclonal antibody

• Goya study

• Obinutuzumab –anti CD20 antibody, more potent than R

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

• 1418 patients

• No difference in response rate, PFS or OS

• More significant toxicity with G-CHOP.

PFS

OS

Additional agents

• ABC DLBCL – poorer prognosis focus of attention

• Some novel agents appear to have preferential activity in ABC type

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

Additional agents

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 + 2xR

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

Management of patients with poor

cardiac function/multiple co-morbidities

INCA study• Multicentre, randomised, phase II trial• 1st line DLBCL• Not suitable for anthracycline

– 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

Molecular Profiling Studies -MaPLe

• DLBCL or grade 3B FL – newly diagnosed

• Samples molecular diagnostic lab, Barts, London

• Molecular profiling

• Basic clinical data collected

• In event of progression, patient screened for targeted treatment

– EZH2 mutation present Epizyme study

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 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

• Tazemetostat (EZH2 histone methyl transferaseinhibitor)

• Single agent, oral therapy

• > 2 previous lines of therapy

• well tolerated

ARGO study

• phase II study, multicentre

• patients who have relapsed post ASCT or unsuitable for transplant

• max 2 previous therapies

• R + gemcitabine + oxaloplatin (RGO) vs

RGO + Atezolizumab

(check point inhibitor)

Follicular Lymphoma

Follicular lymphoma (FL)

• commonest low grade lymphoma, incurable

• treatment not always required at diagnosis

– “watch and wait”

• watch & wait vs rituximab study

– rituximab delay in time to require definitive treatment compared to observation alone

– potential toxicity from infection

FL

• addition of rituximab to chemotherapy improved outcomes

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

PRIMA study

FL

Standard of care:

– Rituximab + chemotherapy eg CVP, CHOP, bendamustine

– Maintenance Rituximab for 2 years

Current Q’s

– can other CD20 antibodies eg Obinotuzumab result in better outcome? (GALLIUM study)

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

GALLIUM study

• Large phase III study, ASH 2016

• Comparison of obinutuzumab (O) + chemo versus rituximab(R) + chemo– chemo - CHOP or CVP or bendamustine

– maintenance O or R for 2 years

• 34% reduction in risk of PFS event in the obinutuzumab arm.

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

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

17. R Marcus et al, ASH 2016

GALLIUM study – reduction in risk of PFS event

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 + lenolidamide

Relapsed FL - GADOLIN Study

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

rituximab refractory

GADOLIN update

Additional 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

Other FL relapse studies

• REBEL study – rituximab and lenolidamide +/- bendamustine

• Epizyme study – tazemetostat – multiple relapsed FL very encouraging results especially if have EZH2 mutation (~70% RR)

T cell Lymphomas

Chemo T study

• CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma

• phase 2, multicentre

• Complete response rates – 1y end point

• Looking for 20% superior response for GEM-P

• Closed early as GEM-P no better than CHOP but more toxic 62% CR/CRu for CHOP vs 46% for GEM-P

Lancet Haematol 2018, Gleeson M et al

ECHELON 2

• CD30 + mature T cell lymphomas

• double-blinded

• CHOP vs CHP + Brentuximab

– Brentuximab – antibody to CD30 conjugated to MMAE

• HDT + ASCT at clinicians discretion

Mantle cell lymphoma

• ENRICH – 1st line

– > 60 years, unsuitable for ASCT

– R-chemo (R-CHOP or R-bendamustine) vs R-ibrutinib

– maintenance R for 2 years (both arms)

– continuous ibrutinib (R-I arm only)

Hodgkin Lymphoma

Hodgkin’s Lymphoma

• ABVD – standard treatment for many years

– 70-80% cure rates

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

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

• advanced stage disease – ABVD x 6

Early stage disease• RAPID study – randomization between no further treatment

and radiotherapy in patients who are PET negative after 3 cycles of ABVD

OS

PFS

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

Advanced stage disease

• RATHL study – using PET scan after 2 cycles to determine treatment

– is it safe to omit bleomycin in those that are PET negative?

– does escalation of therapy to BEACOPP improve outcome in those who are PET +ve?

NEJM, 2016, Johnson P et al

2 cycles ABVD

PET positivePET 2

PET 1

4 cycles BEACOPP-14

or 3 cycles escBEACOPP

RATHL1200 advanced HL

PET 3

RT or salvage 2 cycles BEACOPP-14

or 1 cycle escBEACOPP

No RT

PET positive PET negative

Endpoint : PFS

4 cycles ABVD

PET negative

Randomize

No further treatment

No RT

4 cycles AVD

no bleomycin

RATHL study

• 1203 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%

Conclusion:

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

• respiratory events reduced

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 = 0.48

3 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 = 0.58

3 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)

HR 0.90 (0.47 – 1.74), p =0.76

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% vs43%)

• Serious pulmonary toxicity more common with ABVD (3% vs1%)

NEJM, 2018, Connors. J et al

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

664

670

640

644

623

626

606

613

544

522

530

496

516

476

496

459

474

439

447

415

350

328

334

308

311

294

200

179

187

168

174

153

99

78

85

68

77

62

27

16

24

13

21

12

6

1

4

1

4

1

0

0

0

0

Time from randomization (months)

Pro

bab

ilit

y o

f m

od

ifie

d P

FS

No. of patients at risk:

A+AVD

ABVD

HR 0.77 (95% CI: 0.60–0.98)

Log-rank test p-value: 0.035

A+AVD

ABVD

0.9

0.7

0.5

0.3

0.1

Number of events

Connors, J. et al:Abstract no 0006

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%

– ABVD 2%

0%

20%

40%

60%

80%

A+AVD ABVD

Pat

ien

ts (

%)

Treatment-emergent PN*

Grade 3-4Grade 2Grade 1

2%

7%

<1%

3%

0

1

2

3

4

5

6

7

8

9

10

Category 1Category 2Category 3Category 4

A+AVD ABVD

All

A+AVD ABVD

Grade ≥3

Interstitial lung disease†

Pati

en

ts (

%)

Connors, J. et al:Abstract no 0006

Early interim PET within the German HD18 study

Borchmann P. et al:Abstract no 0737

Advanced stage

Hodgkin lymphoma

PET2 +ve(DS3-5)

PET2 –ve(DS1-2)

eBEACOPP x2

eBEACOPP x4/6

R-eBEACOPP x4/6

eBEACOPP x4/6

Lancet. 2017 Dec23;390(10114):2790-2802

HD15 Lancet. 2012 May 12;379(9828):1791-9

eBEACOPP x2

R

R

Results of German HD18

PET2 negative (DS1-2)

• 5 year PFS 6/8 cycles of eBEACOPP versus 4 cycles

- 90.8% vs 92.2% (ns)

• Early progression/relapse 1.6% in DS1-3 - they will treat DS3 as low risk in future studies

PET2 positive (DS3-5)

• 5 year PFS eBEACOPP vs R-eBEACOPP 89.7% vs 88.1% (ns)

Conclusions:

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

Rituximab is of no additional benefit

Andrew M. Evens et al. Blood 2012;119:692-695

©2012 by American Society of Hematology

Elderly HL - PFS with multi-agent

chemotherapy

Age >70

Cannot perform ADLs

BREVITY study

• untreated HL

• not for standard treatment due to age, frailty, co-morbities

• single agent brentuximab, 3 weekly

• 4 cycles then evaluate by PET/CT

• if CR further 8

• if PR further 4 then if CR, further 8

• total of 12-16 cycles

BREVITY study

• 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 8 patients in CMR 11.9 months

Progression-Free Survival

Brevity study

• 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

• CMR and PFS unsatisfactory

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