1. S1400 Lung Master Protocol SWOG Spring meeting April 13, 2018
LUNG-MAP
S1400 Lung Master Protocol
SWOG Spring meeting
April 13, 2018

2. Welcome SWOG ECOG-ACRIN NRG CCTG Alliance S1400 Master Protocol
Karen Kelly, MD
swog lung cancer committee chair
David Gandara, md
Study Co-Chair, Medical Oncology

3. Study Updates Vassiliki Papadimitrakopoulou, MD
Study Chair, Medical Oncology

4. Where are we now? IRB Approvals: 600 sites
397 sites with at least 1 patient
accrued
Accruals:
1584 patients registered to S1400
764 patients from SWOG sites
1248 patients notified of their sub-study assignment
598 patients registered to a sub-study
As of 4/918

5. Current Status of Sub-Studies
Biomarker-Driven
S1400G [Talazoparib]
Opened 2/7/17
43 pts enrolled
S1400K [ABBV-399]
Opened 2/5/18
6 pts enrolled
Non-Match
S1400I [Nivolumab/Ipilimumab]
Opened 12/18/15
272 pts enrolled
S1400F [MEDI Tremelimumab]
Opened 10/2/17
14 pts enrolled
Ancillary Studies
S1400I PRO – 166 pts enrolled
S1400GEN – 14 pts & 5 PIs enrolled
As of 4/9/18

6. Overview of New Sub-Studies
S1400F: A Phase II Study of MEDI4736 Plus Tremelimumab as Therapy for Patients with Previously Treated Anti-PD-1/PD-L1 Resistant Stage IV Squamous Cell Lung Cancer (Lung-MAP Non-Match Sub-Study)
Presenter: Dr. Mary Redman
S1400GEN: Ancillary Study to Evaluate Patient and Physician Knowledge, Attitudes, and Preferences Related to Return of Genomic Results in S1400
Presenter: Dr. Joshua Roth
S1400K: A Phase II Study of ABBV-399 (Process II) in Patients with c-MET Positive Stage IV or Recurrent Squamous Cell Lung Cancer (Lung-MAP Sub-Study)
Presenter: Dr. Saiama Waqar
This is a lead-in slide for next presenters.

7. S1400F A Phase II Study of MEDI4736 Plus Tremelimumab as Therapy for Patients with Previously Treated Anti-PD-1/PD-L1 Resistant Stage IV Squamous Cell Lung Cancer (Lung-MAP Non-Match Sub-Study)
Mary Redman, PhD
Lead Biostatistician

8. S1400F Overview
S1400F seeks to evaluate the efficacy of MEDI4736 (durvalumab) + tremelimumab, potent PD-L1 and CTLA-4 inhibitors, in such patients.
A “non-match” study for patients who have previously received a PD-1 or PD-L1 inhibitor as a single agent treatment and are not eligible for other Lung-MAP sub- studies.
MEDI4736 (durvalumab) + tremelimumab will be administered intravenously on 1 day for four 28-day cycles. MEDI4736 will be given alone for subsequent cycles.
Treatment will continue in consenting patients until disease progression or intolerable toxicity.
Previously Registered Patients - Patients previously registered to a Lung-MAP sub- study are potentially eligible for S1400F upon progression, if they have also progressed after a single agent PD-1 or PD-L1 inhibitor.

9. S1400F Site FAQs

10. S1400GEN Ancillary Study to Evaluate Patient & Physician Knowledge, Attitudes, and Preferences Related to Return of Genomic Results in S1400
Joshua A. Roth, phd, mha, Fred Hutch
S1400GEN Study Chair

11. S1400GEN: Background & Objective
‘Biomarker-driven’ trials that are guided by genomic results are rapidly increasing in number and may represent the beginning of a new paradigm in clinical trial research in oncology1,2
Complex to design and communicate
Are patients & physicians informed about:
Nuances of return of genomic results?
Relationship between genomic results and sub-study eligibility?
Alternative treatment options (or lack thereof) in sub-studies?
No studies have evaluated knowledge, attitudes, and preferences about genomic profiling in biomarker-driven clinical trials.
Overall Objective: Evaluate patient and physician knowledge, attitudes, and preferences about return of genomic profiling results in the S1400 master protocol trial.
1Redman & Allegra, Seminars in Oncology, 2015; 2Herbst et al. Clinical Cancer Research, 2015

12. S1400GEN: Specific Aims Primary Aim Secondary Aims
Evaluate patient attitudes and preferences about return of somatic mutation findings suggestive of germline mutations in the S1400 master protocol trial.
Secondary Aims
Evaluate S1400 study physician attitudes and preferences about return of somatic mutation findings suggestive of a germline mutation.
Evaluate S1400 patients’ and study physicians’ knowledge of cancer genomics.
Evaluate S1400 patients’ and study physicians’ knowledge of the design of the S master protocol trial.
To explore whether physician and patient knowledge of cancer genomics, attitudes, and preferences about return of genomic profiling findings are correlated.

13. S1400GEN: Inclusion Criteria
U.S. patients enrolled after Revision 12 to the S1400 screening protocol study
(All S1400 sites)
Study physicians with patients who enroll in this ancillary study and complete the patient survey
Able to complete study survey in English

14. S1400GEN: Simplified Schematic

15. S1400GEN: Study Survey
Survey items used in studies of genomic profiling in cancer.
Adapted to context of S1400
Hypothetical questions about germline testing
Patient surveys are targeted to take minutes to complete (phone)
Physician surveys are targeted to take <15 minutes to complete (online)

16. S1400GEN: Study Survey continued
Example: I will now ask you about whether you would want to know certain kinds of genetic test results if they were offered to you.

17. S1400GEN: Study Accrual as of 4/9/18
Patient Participants
Physician Participants
Completed Consent
Survey Completed
% Accrual Goal
Non-M/U Sites 31 12
8% (Goal=150)
M/U Sites 3 2
4% (Goal=50)
Total 34 14
7% (Goal=200)
Completed Consent
Survey Completed
% of Accrual Goal
Total 5
17% (Goal=30)
M/U = Minority/Underserved Sites As of 4/9/18

18. S1400GEN: Notes for Sites
Study approved by CIRB in Revision 12 on 1/31/18 (Section 15.5 & 18.1f)
Consent for S1400GEN is provided in an appendix to the S1400 master protocol screening and pre-screening consent forms (pages 11-12).
Patient participants should be provided a hard copy of study survey to allow them to follow along during the telephone interview.
Go to CTSU website 
Protocols > S1400 > Documents > CIRB Documents > Amendment Reviews > Revision 12 (Protocol Version Date 01/08/18) > Support Documents.
If having trouble, contact Crystal Miwa

19. S1400GEN: Next Steps
Complete accrual of 200 patient & 30 physician participants by 1/30/2019
Using survey responses, explore the following:
Knowledge of cancer genomics and return of results in the S1400 trial
Distinctions in somatic vs. germline mutation testing
Types of genomic results that are returned in the S1400 trial
Likely outcomes of ‘matched’ and ‘non-matched’ treatments
Attitudes about return of genomic results in the S1400 trial
Return of different types of genomic findings
Open-ended questions provide deeper insights into patient attitudes (motivations and concerns) about participating in the S1400 trial
Preferences for return of genomic results in the S1400 trial
Preferences for return of different types of genomic findings
Preferences for return of results to family members in the event of somatic mutation findings suggestive of germline mutation
Preferences for return of genomic findings to family members in the event of their death prior to receiving results themselves

20. S1400GEN: Thank You!
S1400GEN Study Chair Joshua A. Roth, PhD, MHA, Fred Hutch
Dawn Hershman, MD, MS, Columbia University
Scott D. Ramsey, MD, PhD, Fred Hutch
S1400GEN Primary Fred Hutch Study Coordinator Debbie Delaney,
S1400GEN Primary SWOG Study Contact Crystal Miwa,

21. S1400K A Phase II Study of ABBV-399 in Patients with c-MET Positive Stage IV or Recurrent Squamous Cell Lung Cancer (Lung-MAP Sub-Study)
Saiama N. Waqar, MBBS, MSCI, Washington University
Susanne M. Arnold, MD, University of Kentucky

22. S1400K: Overview
c-MET overexpression is seen in 30% of patients w/ lung squamous cell carcinoma.
Biomarker-driven study for patients with Stage IV or recurrent squamous cell lung cancer, who have c-MET positive squamous cell tumors.
c-MET testing using Ventana SP44 rabbit monoclonal antibody
IHC cutoff H score ≥ 150
ABBV-399 (Process II) is a first-in-class antibody-drug conjugate targeting c-MET
This delivers a direct anti-mitotic effect without relying on MET pathway inhibition.
Overall Objective: Seeks to evaluate the overall response rate (ORR) with ABBV in patients with c-MET positive SCCA.

23. S1400K: Schema Lung-MAP Screening/ Prescreening Registration
C-MET positive (H score ≥ 150)
Sub-Study Assignment to S1400K
S1400K Registration
Stained by ARUP
Scored by Flagship Biosciences
ABBV-399 continued till progression or intolerable toxicity
Accrual goal: 44 patients
Activated: 2/5/18
First patient enrolled: 3/16/18
Go to: for current status

24. S1400K: Objectives Primary Objective Secondary Objectives
To evaluate the ORR (confirmed and unconfirmed, complete and partial) with ABBV (Process II) in patients with c-Met-positive lung squamous cell carcinoma.
Secondary Objectives
To evaluate investigator-assessed PFS and OS with ABBV-399 in immunotherapy-exposed and relapsed patients with c-Met positive squamous cell tumors.
To evaluate the ORR with ABBV-399 in immunotherapy-exposed and relapsed patients with c-Met positive squamous cell tumors.
To evaluate IA-PFS, and OS in all patients with c-Met positive lung squamous cell carcinoma .
To evaluate the duration of response (DoR) with ABBV-399.
To evaluate the frequency and severity of toxicities associated with ABBV-399.

25. S1400K: ABBV-399 Mechanism of Action
ABBV-399 is an antibody drug conjugate (ADC) comprised of:
ABT-700, a humanized recombinant immunoglobulin G kappa that targets c-Met
Conjugated via a cleavable valine-citrulline (vc) linker to
Cytotoxic microtubule inhibitor monomethylauristatin E (MMAE)
MOA: targeted delivery of cytotoxin to tumor via c- MET receptor
Direct killing of tumor cells

26. S1400K: ABBV-399 Administration
Route: ABBV-399 is to be administered intravenously
Dose: mg/kg IV over 30 minutes ± 10 minutes on day 1
Cycle duration: 21 days
Administration: With a 0.2 micron low protein binding in-line filter
Premedication: None required, allowed per ASCO guidelines
Supportive care: May be given as indicated by the current ASCO guidelines
Disease assessment: Every 6 weeks ± 7 days
Prohibited medications: Strong CYP3A inhibitors (increase exposure to MMAE)
Grapefruit/grapefruit juice, atazanavir, indinavir, nelfinavir, ritonavir, saquinavir, clarithromycin, telithromycin, itraconazole, ketoconazole, fluconazole, voricaonazole, fluvoxamine, and nefazodone

27. S1400K: Eligibility Criteria
c-MET positive (H score ≥ 150 using Ventana SP44 assay)
Peripheral edema Grade 1 or less
Peripheral neuropathy Grade 1 or less
No prior c-MET pathway inhibitors
Albumin ≥ 3.0 g/dL
Adequate hepatic function
AST an ALT ≤ 2.5 X ULN
GGT ≤ 5 X ULN
< 50% of liver occupied by metastatic disease
Liver lesions <10cm
Excludes patients who are pregnant or nursing
Must agree to give blood samples for pharmacokinetic analyses

28. S1400K: Stratification Factors
Patients will be stratified into two cohorts based on their prior exposure to anti-PD-1/PD-L1 therapy. The two cohorts are defined as:
Cohort 1 (anti-PD-1/PD-L1 Naive):
Patients who have not been exposed to an anti-PD-1/PD-L1 therapy
Cohort 2 (anti-PD-1/PD-L1 Exposed):
Patients with a history of anti-PD-1/PD-L1 therapy

29. S1400K: Criteria for Removal from Treatment
Progression of disease or symptomatic deterioration (as defined in Sections 10.2d and 10.2e of S1400K).
Upon progression, the S1400 Request for New Sub-Study Assignment Form may be submitted to receive a new sub-study assignment (see S1400K Section 14.0).
Unacceptable toxicity.
Treatment delay for any reason > 42 days.
The patient may withdraw from this study at any time for any reason.

30. S1400K: Dose Modifications for ABBV-399
Dose reductions are allowed on ABBV-399
Dose may be reduced in 0.3 mg/kg increments
Dose interruptions and discontinuations are allowed to manage toxicity
Maximum dose delay is 42 days for any reason
General dose modifications:

31. S1400K: Dose Modifications/Holds Infusion Reactions

32. S1400K: Dose Modifications/Holds Neuropathy

33. S1400K: Dose Modifications/Holds Marrow Suppression

34. S1400K: Dose Modifications/Holds HYPOALBUMINEMIA AND PERIPHERAL EDEMA

35. S1400K: Contacts Study Chairs: Dr. Saiama N. Waqar
Washington University School of Medicine
Dr. Susanne Arnold
Markey Cancer Center, University of Kentucky
Questions:
Eligibility/Data Submissions:
Treatment/Toxicity:
Protocol/Regulatory: and

36. Roy herbst, MD, phd S1400 Study Co-Chair, Medical oncology
Future Studies
Roy herbst, MD, phd
S1400 Study Co-Chair, Medical oncology

37. Future Studies Future Studies
LungMAPScreen – New Lung-MAP Screening Study Version 2
Includes all histologies (NSCLC)
Establishes an immunotherapy combination (IO) platform
Includes ctDNA Translational Medicine study
Submitting to CTEP in April
S1800A – Ramucirumab + Pembrolizumab (in Protocol Development)
Non-match sub-study
All NSCLC
First sub-study in IO platform
S1400L – Rucaparib (in Concept Development)
Biomarker-driven sub-study enrolling all NSCLC

38. Expansion of Lung-MAP Previously-treated Stage IV or Recurrent
Non-Small Cell Lung Cancer
(all histology NSCLC)
Immunotherapy or Chemotherapy Relapsed/Refractory Patients
Expansion of
Lung-MAP
Centralized NGS* Biomarker Profiling
Biomarker-matched* Sub-studies
Non-Matched Sub-studies
Biomarker 1 Positive
…Biomarker n Positive
IO Naïve
(squamous only)
IO Relapsed/Refractory
Collect tissue for Immuno Biomarker Profiling
Sub-study 1
Biomarker-driven
Therapy
…Sub-study n
Biomarker-driven
Therapy R
Stage 1:
Nivolumab + Ipilimumab V.
Nivolumab
Investigational therapy 1
Investigational therapy n
IOC Sub-study 1
IO combo 1
…IOC Sub-study m
IO combo m
Stage 2: R R
Investigational therapy 1
Standard of Care
Investigational therapy n
Standard of Care
*Currently, biomarkers are defined by NGS. Though approaches such as c-MET IHC
or Immunotherapy biomarkers may be used
IOC = Immunotherapy Combination

39. Screening Study ctDNA TM
Philip C. Mack, phd
S1400 Translational Medicine co-Chair

40. Liquid biopsies: cell-free circulating tumor DNA
Advanced malignancies shed DNA into circulation
DNA is highly fragmented
Stable for a few hours
Technology is already in routine clinical practice
Identify emergent resistance factors
Expand biomarker detection in patients with insufficient biopsies
Monitor disease progression & evolution
Integration into LungMAP

41. Results: GH360 ctDNA Genomic Landscape in Lung Adenocarcinoma
EGFR Driver Mutations
52% E19 del
34% L858R
4% E20 ins
10% other
G719
L861
S768
E709
Other rare mutations
8,388 NSCLC cases reported at WCLC 2016 (Mack et al, OA06.01)

42. Screening ctDNA Translational Medicine
Cell-free, circulating DNA will be isolated from patient plasma
Utilize FoundationACT plus (Foundation Medicine)
Hybrid-capture, next-generation sequencing technology
Point mutations, small insertions and deletions, chromosomal rearrangements and copy number/amplification events in 62 genes
An assessment of tumor mutation burden (TMB) will be conducted using ctDNA.
Initial Goal: The presence of tumor-specific mutations in baseline plasma specimens will be correlated with results obtained from tumor tissue. The clinical utility of plasma-based mutation testing will be rigorously assessed prior to utilization for subArm assignment.

43. Screening ctDNA Collection Details
Special tubes will be provided in kits
Roche Cell-Free DNA blood collection tubes (8.5ml) x2
Minimal in-lab processing required
Label tubes
Collect whole blood
Gently invert 10 times
Place in specimen shipping kits (provided)
FedEX overnight (Fridays okay) at room temperature (DO NOT FREEZE)
Send same day or next day
Standard collection time point: Baseline
Within one week of tissue biopsy (+/- 7 Days) – Prior to treatment

44. Tumor evolution and drug target identification
Future S1400 sub-studies will incorporate more advanced liquid biopsy analyses
Tumor evolution and drug target identification
Longitudinal analysis from serial blood draws
Global tumor heterogeneity
Molecular response to therapy
Changes in total ctDNA amounts
Changes in relative allele frequency
Emergence of resistance mechanisms

45. Treatment-induced changes in plasma mutant allele frequencies
Baseline
(pre-treatment)
Molecular
Response
First observation of emergent resistance
Clinical
progression
Blue: EGFR L858R
Orange: EGFR T790M

46. Site Coordinators Committee (SCC)
Lavinia Dobrea RN, MS, OCN
Site Coordinator Committee co-Chair

47. SCC Mission
To represent study site staff at the nursing, CRA, data management, and regulatory levels by providing feedback to and from the study leadership to enhance accrual and improve study management.

48. SCC Activities Review and recommend accrual materials and strategies
Review changes to study procedures and updates to data collection forms
Provide content for the Lung-MAP newsletter
Participate in Update meetings
Present at Oishi Symposium
Assist in promoting the study and encouraging accrual
Provide overview of what was presented at Oishi Symposium.

49. SCC Activities
Assist with planning, development, and implementation of staff training tools
Progress Notes for Pre-Screening, Screening, Progression, Sub- studies
Patient AE Log
RECIST Tracker
Examples of drug order templates
CT Reminder
Data Entry guidelines
NOW available on the S1400 Abstract Page under S1400 Resources on the SWOG website (

50. SCC Activities
Review & provide insight from a site perspective on the Future Re-Design of S1400 and S1800
Assist in the creation of patient materials
Providing relevant site information via webinars

51. Send us the information or materials and
Questions?
Have a concern or question?
Want an opportunity to work with the Site Coordinator Committee members?
Do you have an accrual strategy or materials you would like to share?
Do you have tracking forms or procedures to help you manage Lung-MAP at your site?
Send us the information or materials and
include your name, study site, and contact info.

52. Contact us: LungmapSCC@crab.org

53. David gandara, MD S1400 Study Co-Chair, Medical oncology
Q & A Session
David gandara, MD
S1400 Study Co-Chair, Medical oncology

54. Questions? Thank you for your time.
The slides presented today will be available on the SWOG website S1400 Protocol Abstract page Other Study Materials S1400 Group Meeting Materials link