Moving forward, where are we with Clinical Trials?

(1)

Moving forward, where are we

with Clinical Trials?

Dennis A. Wigle

Division of Thoracic Surgery Mayo Clinic

AATS/STS General Thoracic Surgery Symposium Sunday, April 27th ₂₀₁₄

(2)

Where are we with Clinical Trials?

(Thoracic Surgical Oncology)

Overview:

• Funding status at NCI for co-op group studies

• Alternative funding routes

• Current studies

• Trials pipeline – concepts on the horizon

• Reflection: are we really addressing key questions in thoracic surgical oncology?

(3)

Where are we with Clinical Trials?

Tough times for surgical trials:

• Little interest except from surgeons

• ACOSOG officially dead

• Recent demise of high profile trials (Z4099)

• Funding crunch at NCI affecting trials network despite re-organization

(4)

Number of Alliance Active Studies

Excluding LCTB

year

No. Active

(5)

Where are we with Clinical Trials?

Potential opportunities:

• Currently no/little AATS/STS involvement as a coordinating force

• Examples like the Alliance Thoracic Surgery Group

• Industry relationships

• Need to stay engaged – particularly for multimodality studies

(6)

Where are we with Clinical Trials?

Alternative funding routes:

• R01/R21 funding

• Foundation $$

• Industry relationships

(7)

Highlighting 2 studies:

• CALGB 140503 (Alliance)

• RTOG 0849

(8)

CALGB 140503

A Phase III Randomized Trial Of Lobectomy

Versus Sublobar Resection For Small (≤ 2

Cm) Peripheral Nonsmall Cell Lung Cancer

Study Chair: Nasser Altorki

Activated: 6/15/07 # CALGB / CTSU Sites Open: 48 / 104 Target / Current Accrual: 692 / 411 Accrual Last 90 / 30 Days: 17 / 7

(9)

CALGB 140503

Pre-Register Suspected Peripheral T₁N₀ lung cancer ≤ 2cm

RANDOMIZATION

Limited resection (Wedge or segmental)

Stratification : Tumor size (< 1cm, 1-1.5cm, 1.5-2.0cm) Histology (Sq. cell, AdenoCa, Other)

Smoking status (Never, Former, Current) Lobectomy

Confirm N₀ by Frozen: Right: Levels 4,7, 10 Left: Levels 5 or 6, 7, 10

(10)

Imaging Study Objectives

•Correlate preoperative CT and PET

characteristics with outcome

•Determine false negative rate for PET in

hilar and mediastinal nodal mets

•Determine utility of annual follow-up CT

(11)

RTOG 0839:

Randomized Phase II Study of Pre-operative

Chemoradiotherapy +/- Panitumumab Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIA, N2+) Non-Small Cell Lung Cancer

Primary Objective:

Mediastinal nodal clearance following completion of induction chemoradiation +/- panitumumab

Surgical PI - Jessica Donington

(12)

(13)

• ALCHEMIST

• Neoadjuvant immunotherapy

(14)

ALCHEMIST

Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trial

(15)

Trial Protocol Details

E4512 A081105 A151216

Target ALK+ EGFRmut Registry

Prevalence ~5% ~10% all comers

n 336 410 6000 – 8000 Primary Endpt DFS OS --Power 80% 85% --One-sided α 0.025 0.05 --HR 0.67 0.67 --Adjunct Peripheral screening for ALK; RTPCR to identify fusion partners Targeted sequence and kinome analysis; PRO and QOL Extended sequencing for additional targets; correlation with local testing

(16)

Register post‐op Register pre‐op Collect blood; central EGFR & ALK genotyping Assess & obtain FFPE tissue Patients on adjuvant trials followed separately Follow q6 months for 5 years ALCEMIST screening trial

Proposed ALCHEMIST schema

SOP for FFPE tissue

(17)

Stage IB- IIIA NSCLC

Complete Surgical Resection Stage IB- IIIA

NSCLC Complete Surgical Resection Adjuvant Therapy (if indicated) Adjuvant Therapy (if indicated) Crizotinib X 2 years Crizotinib X 2 years Placebo Placebo

Screen for ALK+ cancers

ALCHEMIST-related Adjuvant Therapy Trials (A081105 & E4517)

Stage IB- IIIA NSCLC

Complete Surgical Resection Stage IB- IIIA

NSCLC Complete Surgical Resection Adjuvant Therapy (if indicated) Adjuvant Therapy (if indicated) Erlotinib X 2 years Erlotinib X 2 years Placebo Placebo

Screen for EGFR mutation+ cancersScreen for EGFR mutation+ cancers R a n d o m i z e R a n d o m i z e A081105 E4517

(18)

ALCHEMIST aims

Primary objectives

1. Determine feasibility of central EGFR

and ALK genotyping to facilitate

accrual to adjuvant studies

2. To collect research-grade tissue for

advanced genomics by the Center for

Cancer Genomics (CCG) at the NCI

(19)

ALCHEMIST aims

Secondary objectives

1. To characterize the natural history of

resected EGFR and ALK wild-type lung

cancers

2. To cross-validate local EGFR and ALK

assays with a central standard

(20)

Evaluation of Tumor Response

after Neoadjuvant Nivolumab

with or without Ipilimumab in

Non-small Cell Lung Cancer

(NSCLC)

(21)

Figure 1 Mechanism of action of cancer vaccines

Drake, C. G. et al. (2013) Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer

(22)

Figure 2 Immune checkpoint blockade

Drake, C. G. et al. (2013) Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer

Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2013.208

(23)

Concept

• Histologically or cytologically documented

NSCLC

• Clinical stage IB (≥4cm per CT), Stage IIA/IIB,

or Stage III (N0-2) amenable to surgical resection.

• Patient must be deemed a surgical

(24)

Concept

• Arm A: Nivolumab 3 mg/kg IV every 2 weeks

x 3 doses

• Arm B: Nivolumab 3 mg/kg IV every 2 weeks

x 3 doses plus Ipilimumab 1mg/kg IV one dose day 1

• Followed by surgery at ~4-6 weeks

• Primary objective: Evaluate whether the combination of neoadjuvant nivolumab plus ipilimumab increases the tumor response rate

compared to nivolumab alone from 20% to 30% in stage 1B, 2 or 3A non-small cell lung cancer.

(25)

Concept

• Imaging, molecular correlates in resected

tumor

• Opportunity for adjuvant immunotherapy

regimen for responders after completion of conventional Rx

(26)

Lung e-tumor board frequent dilemmas:

• Rx for mesothelioma in fit patient?

• Best management of IIIA NSCLC?

• Early stage NSCLC in the compromised patient?

• Role of SBRT in early stage NSCLC?

• Surgery post SBRT/conventional rads?

• ….and so on

Are we really addressing key questions

in thoracic surgery?

(27)

• Thinking of good trials is easy, getting them done is hard work

• Many opportunities to get involved

• Institutional co-op group

• Multi-center alliances

• Single institution studies

• GTSC trials list – we will update for 2014

http://gtsc.org/home/clinical-trials/

(28)

• Need to stay engaged and participate

• Treat patients on study as much as possible

• We need you to advance the science of what we do

(29)

Moving forward, where are we with Clinical Trials?