12h20 gorlia thierrychallenges and pitfalls in designing...

Challenges and pitfalls in designing clinical

trials in the CNS metastases field.

Dr. Thierry Gorlia, PhDEORTC Lead

Statistician

Factors influencing the choice of endpoints

• Patients with solid tumors may differ in prognosis and competing risk of extracranial progression.

• The trial setting (Phase II (response) vs Phase III trials (PFS/OS)

• Type of intervention (CNS-directed vs systemic therapies, RT vs CT)

Requiring ad hoc end points.

Soffietti R. et al. CNS Oncol. 2017 Oct;6(4):243-246.

Specifics of trials for brain metastases

• Goal is rarely improvement in survival, as most patients die of extracranial disease

• Most assessed treatments are local treatments targeting the brain disease• Prophylactic treatment (e.g. PCI in M0) à goal is to prevent occurrence of brain metastases• Palliative treatment (brain metastases in place) à goal is often to preserve function and/or reduce the risk of

progression of brain disease

Specifics of trials for brain metastases

• Other disease sites (primary or other metastases)• either in place (and controlled)• or removed prior to entry in the trial

àCompeting risks: progression elsewhere in the body may cause the patient to die (of cancer) without disease evolution inside the brain

àHeterogeneity of outcomes according to the type of primary & by treatments given to control other sites of PD (often assumed not to cross BB-barrier)

• Small risk that the patient dies of a cause unrelated to cancer (rare)

Specific role of prognostic factors

• The knowledge of prognostic factors is critical in order to identify subgroups of patients with different outcomes

• As stratification factor or inclusion criteria or adjustment factors in analyses.

Sperduto PW et a. JAMA Oncol. 2017;3(6):827-831.

Lung-molGP

Key issues in imaging brain metastases

• Modalities and frequency of assessment, • Type and magnitude of change used to define response or

progression of disease, • The incorporation of steroid use and neurological

symptoms/signs• The ability to differentiate tumor-related and treatment-related

changes• The interlesional variability of response to treatment can render

problematic the evaluation of response in multiple metastasesSoffietti R. et al. CNS Oncol. 2017 Oct;6(4):243-246.

Past experience within EORTC

• EORTC 22993-08993: PCI in ED NSCLC (Slotman et al. NEJM 2007 &

JCO 2008)

• EORTC 22952-26001: WBRT for 1-3 brain mets from solid tumor after

resection or radio-surgery (Kocher JCO 2011, Soffietti submitted to JCO)

• Design of SIB trial (22111-26111)

• Design for testing Sunitinib combined with WBRT in brain mets of breast

cancer not suitable for resection (10095)

• Earlier phase II studies by Postmus et al. (08841, 08873…) in SCLC

(WBRT, Teniposide, Etoposide); PCI study with EULINT group…

Possible endpoints

« Global » endpoints• Overall survival• Progression-free survival (all disease sites)

« Brain-specific » endpoints• Incidence of (symptomatic) brain mets (if prophylactic)• (Symptomatic) progression of metastases (if therapeutic)

« Quality of living » endpoints• Survival with WHO PS ≤ 2 (or KPS≥70) “independent life”• Neurological function scores• Quality of life, ...

? Sensitivity to brain trt effects

? Relevance if no effect on symptoms/QoL

? Reliability of measurements, drop outs, biases

EORTC 22993-08993: Phase III of PCI* in Extensive Disease SCLC

l Cytologically or histologically proven SCLCl Response after 4 to 6 cycles of initial

chemotherapyl No evidence of brain metastases

or leptomeningeal metastasesl No prior radiotherapy to the brain and head and

neck areal No use of corticosteroidsl 18 £ Age£ 75 years, WHO PS £ 2

l Primary endpoint: time to symptomatic brain metastases

l Secondary endpoint: l Quality of life and MMSEl OSl Time to extracranial PDl FFS** (any PD or death)l Acute toxicity

PCI*

No furtherradiotherapy

RandomInduction

Chemotherapy(4-6 cycles)

Response

5 weeks*PCI: Prophylactic cranial irradiation; **FFS: Failure Free Survival

Slotman BJ. J Clin Oncol. 2009 Jan 1;27(1):78-84.

Protocol statistical considerations

• It is expected that without PCI, 40% of the patients develop brain metastases within 3 year.

• To demonstrate decrease in rate of symptomatic brain metsfrom 40% at 3 years to 20% (HR=0.44, 2-sided a=0.05, power 80%) à 50 events of symptomatic BM needed.

• Anticipating 40% death rate by year 3à 287 patients are planned to enter to get the 50 events needed.Visits after baseline: at 6 wks, 3 months, 6 months, 9 months and 12 months

then q6 months + QLQ-C30 and BN20 at each visitSlotman BJ. J Clin Oncol. 2009 Jan 1;27(1):78-84.

Overall Survival in control group

(months)0 4 8 12 16 20 24 28 32 36

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment125 143 90 43 15 3 2 1 0 0 Control

At 6 m44.6%

At 1 y13.3%

Control At 3 y.. 0%

Assumed 40% dead by year 3àway too optimistic à40% dead by month 4!

%


Symptomatic BM in control group

(months)0 4 8 12 16 20 24 28 32 36

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment59 143 74 36 11 2 1 1 0 0 Control

At 6 m32.0%

At 1 yr40.4% Control

Assumed 40% by year 3à 40% reached by year 1 already!

Flat because nobody alive without PD elsewhere

%


Follow-up schedule

(months)0 3 6 9 12 15 18 21 24

0102030405060708090

100

O N Number of patients at risk : Treatment125 143 115 58 36 15 3 2 1 Control

à QoL analyzable only to month 9à More exams in 3-9m would have been useful

%


Compliance to QoL: drop outs!

N alive/arm

% forms completed

Baseline 140 93.7%At 6 weeks 60.0%At 3 months 110 54.5%At 6 months 60 60.8%At 9 months 35 46.3%At 1 year 15 48.9%

Missing/drop outs ~ 40%Upon symptomatic BM?


Cumulative incidence of symptomatic BM

(months)0 4 8 12 16 20 24 28 32 36

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment59 143 74 36 11 2 1 1 0 024 143 97 48 24 12 5 3 2 2

ControlPCI

PCI

Control

• More exams early when trt effect on BM appears• Study should have been monitored more closely, à we may have done with less patients as events accumulated faster than planned

%


Failure-free survival

(months)0 3 6 9 12 15 18 21 24 27

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment

137 143 62 20 8 1 1 0 0 0129 143 79 30 13 6 3 3 2 1

ControlPCI

Hazard Ratio: 0.76 (95%CI: 0.59, 0.96)Median: 12.2w à 14.8w (+2.6w)

15.5%

At 6 m23.4%

Logrank P=0.022

PCI

Control

à More meaningful to patients?à Less sensitive to treatment effects,à esp.if PD at other sites before sympt BM

%

EORTC 22952-26001: No RT vs WBI for 1-3 brain metastases from solid tumor after surgical

resection (Sx) or radiosurgery (RSx). l Primary endpoint: Time to deterioration of the WHO

PS to WHO PS> 2 (= Survival with WHO PS£2)l Secondary endpoints: OS, QoL, PFS, Time to

neurological progressionEligibility:l 1 or 2 (or 3) BM within 3 weeks of (radio)surgeryl Stable systemic cancer for the last 3 months (= absence

of symptomatic and radiologic progression outside the brain)ORAsymptomatic synchronous primary tumor without metastases outside the CNS, or patients with unknown primary tumor

• Complete resection of brain mets or for RS, mets than can be radioresected

RadioSurg

No further RT

WBI

Surgery

No further RT

WBI

OR

R

R

Kocher M et al. J Clin Oncol. 2011 Jan 10;29(2):134-41

EORTC 22952-26001:Trial sample size and objectives

l To show that WBI improves the survival with PS £ 2 @6m from 50% to 61% (HR=0.71)

à 280 events (death OR WHO PS>2)

l However, as the event rate in the control arm was LOWER than anticipated (40% @6m instead of 50%), the total number of patients was increased from 340 in the original protocol to 359 (to observe the total number of events).

Adequate study monitoring à identified drop outsà prevented to close the trial with only few patients in follow-up, having to wait trial results “forever”à 280/340 : little room for the happy few and drop outs


22952-26001: Survival results

HR = 0.96 (CI: 0.76–1.20)P=0.71

63.0% (95%CI: 55.4-69.6)66.9% (95%CI: 59.4-73.2)

HR = 0.98 95%CI: 0.78–1.24)P=0.89

66.2% (95%CI: 58.8-72.7)70.2% (95%CI: 62.9-76.4)

(months)0 6 12 18 24 30 36 42 48 54 60 66

0

10

20

30

40

50

60

70

80

90

100

Treatmentno RTWBI

Survival with PS<=2

%

(months)0 6 12 18 24 30 36 42 48 54 60 66

0

10

20

30

40

50

60

70

80

90

100Overall Survival

%

Treatmentno RTWBI

66.9% OS with PS£2 vs 70.2% OS and 63.0 % OS with PS£2 vs 66.2% OS

àWHO PS>2 accounts for

only 3-4% of events @6m

àMissing reports of WHO

PS at last visits? Infrequent

visits?


= first event ofWHO PS>2Death with PS£2

Time to intracranial progressionCompeting Risks: death, extracranial progression

Time to extracranial progressionCompeting Risks: death

22952-26001:Time to intra/extra cranial PD

(months)0 6 12 18 24 30 36 42 48 54 60 66

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment100 179 47 21 13 10 6 5 4 3 2 260 180 75 36 24 17 14 11 8 8 5 3

no RTWBI

CI of 22952: Time to intracranial progressionCompeting Risks: Death, Extracranial progression

%

Gray test: p<0.0001

54.2% (95%CI: 46.9-61.5)

31.2% (95%CI: 24.3-38.0)

(months)0 6 12 18 24 30 36 42 48 54 60 66

0

10

20

30

40

50

60

70

80

90

100

O N Number of patients at risk : Treatment111 179 75 40 22 16 11 8 7 6 4 2110 180 87 51 35 23 17 13 9 8 5 3

no RTWBI

CI of 22952: Time to systemic progressionCompeting Risk. Death

%

Gray test: p=0.96

60.5% (95%CI: 53.2-67.8)

60.3% (95%CI: 53.0-67.5)

à Relevant endpoint if symptoms not relieved? (no QOL benefit seen)

à Extracranial PD very early àalso impacts WHO PS and OS.


Progression Free Survival

Meaningful to patients ?Sensitive to trt effects, (if PD at other sites first)?

26.3%

42.2%

WBI

no RT

HR = 0.71 (CI: 0.58 – 0.88), P=0.002

Median: 20.0w (95%CI: 17.0-.26.5)Median: 14.8w (95%CI: 13.5-17.0)

=+5weeks

(months)0 6 12 18 24 30 36 42 48 54 60 66

0

10

20

30

40

50

60

70

80

90

100

%

PFS = first event ofIntracranial PDExtracranial PDDeath in absence of PD

Sequence of events in 2295210-14% death as first event32-46% with PD outside brain as first eventà 40-50% « other events »à Will not be affected by BM treatmentà sets a “cap” on benefit that can be expected

PFS-6 will never be > 50-60% even if eradicating BM.

Same mechanism for alive with WHO PS£2

Important elements to consider for TTE endpoints

• Frequency of assessment should be min Δmedians/2 (eg: to detect a 3 month shift: 6 weekly assessments)

• Impact of compliance to schedule à systematic deviations from schedule may cause artificial differences in survival curves

• Open label studies à risk of bias towards earlier assessments and diagnosis of PD (WHO PS worsening) in the arm with no/less treatment of the brain?

Impact of deviations from schedule

Both treatment groups are scheduled to have outcome assessments every 8 weeks; however, Drug B has an average delay of 5 days at each assessment time. Both groups have an actual median progression-free survival (PFS) of 18 weeks; however, the reported PFS of Drug B is clearly better, only because of the increased time to each assessment

BA

Gignac GA et al. Cancer 2008; 113(5): 966-74

“Quality endpoints”

• Subjective endpoints: QOL, WHO PS, Neurological function?• Blinding not possible

Assessment by a staff unaware of the treatment received?• Inter-rater variations? (eg: WHO>2 vs KPS<70 vs NFS?)• Influence of factors other PD and protocol treatment? (steroids,

anti epileptics on NF etc..)• Most sensitive and specific tools? (not MMSE)

• Neurologic Assessment in Neuro-Oncology (NANO) or PRO approach, such as the MD Anderson Symptom Inventory Brain Tumor Module.

• Prospective collection on seizures.

“Quality endpoints”

• Patient’s drop off before assessment• Eg: 22952: paradoxical impression that worse WHO PS at

baseline à better compliance (because QOL until endpoint reached, and endpoint includes WHO PS…)

• Impact of tumor site and disease load at baseline à different baseline scores, different timing of event à stratification needed

Design of new studies

• Stratification factors: RPA, site of primary, tumor load• Endpoints:

• Clinically meaningful• Uniformly assessed (as much as can be)• Keep biases away (by “pseudo-blinding”)

• Frequency of assessment: more intense early on, less than the difference to detect.

Design of new studies

• Compliance to scheduled assessments is crucial!• Assumptions underlying sample size & target difference

• Mind the “cap effect” due to competing risks• Monitor hypotheses, drop outs and competing risks during

study

Thank you

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