Clinical trial NCT02963610
Conditions: Relapsed or Refractory Solid Tumors Nonsmall Cell Lung Cancer
Sponsor: Fox Chase Cancer Center
Start date: 2017-03-29; Completion date: 2018-03-20
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
For the phase I component of the trial a classic 3 + 3 dose escalation design will be utilized, with a fixed dose of pembrolizumab and an escalating dose of the lenalidomide. The patient population will all have histologically confirmed advanced solid tumor malignancy. The primary endpoint for the phase I component of this protocol will be determining the maximum tolerated dose (MTD) of lenalidomide in combination with pembrolizumab.

The phase II component of this trial will utilize a two stage design, initially enrolling 13 patients, followed by 13 more patients if the early stopping criteria are not met. The target population will include patients with histologically confirmed diagnoses of non-small cell lung carcinoma, regardless of histologic subtype; who have completed one line of standard therapy. The primary endpoint for the phase II component of this protocol will be determining efficacy as measured by progression free survival (PFS)

Detailed description:
Phase I The study will plan to enroll 3 patients in an initial cohort, to receive the dose level 1 of lenalidomide (10 mg PO) on days 1-14 of a 21-day cycle, and pembrolizumab (200 mg IV) on day 1. Patients will be evaluated for toxicities after initiation of treatment. If there are no DLTs for the initial 3 patients after one cycle, the next dosing cohort will open, with another 3 patients. Similarly, if the second cohort of patients receives the dose level 2 of lenalidomide (15 mg) for one cycle without DLT, then the third and final cohort will open. When the third cohort testing the dose level 3 of lenalidomide (20 mg) has completed one cycle, the phase I component of the trial will be completed. Standard phase I, 3 + 3 design rules will be utilized as follows: if 1 out of 3 patients experiences a DLT at certain dose level, then 3 more patients will be enrolled at the same level. If 2 out of 6 patients experience DLT at a certain dose level, 3 additional patients are added at the next lower level. Dose reduction is continued until at most 1 of 6 patients experiences DLT. The highest level with at most 1 of 6 patients DLT will be declared MTD. If no dose level achieves this criterion the trial will be discontinued for excess toxicity.

Phase II A pre-treatment (archival) and fresh tumor sample will be needed for participation in trial. PD-L1 expression levels in both samples will be determined to assess the role of chemotherapy on expression level and pattern of this biomarker. Baseline blood samples will be collected for immunologic correlates prior to treatment on Day 1 of Cycle 1 and post treatment at 2, 4, 24 hours. Samples will also be collected prior to treatment on Day 1 of Cycle 2, and at time of progression. Baseline CT scan of the chest and abdomens will be obtained within 30 days prior to the initiation of cycle 1. CT scan with contrast or MRI with contrast of the brain will also be obtained within 30 days prior to the initiation of cycle 1. Time to progression will be measured with disease imaging following every 2 cycles of therapy with a three-day window (+ or -). Patients will continue treatment until disease progression or unacceptable toxicity or two years of therapy. Overall survival will be assessed every 3 months during long term follow up

Arms: arm 1: Phase I The treatment will be given on a 21-day cycle, with a dose of pembrolizumab given on day1(IV) and doses of lenalidomide given on day 1-14 (orally). The dose of pembrolizumab will be fixed at 200 mg. The dose of lenalidomide will depend upon the patient cohort. Cohort 1 will receive 10mg, Cohort II will receive 15mg and cohort 3 will receive 20mg of lenalidomide.

Phase II The treatment will be given on a 21-day cycle, with a dose of pembrolizumab given on day1(IV) and doses of lenalidomide given on day 1-14 (orally). The dose of pembrolizumab will be fixed at 200 mg. Maximum Tolerated Dose (MTD) of lenalidomide as determined by the Phase I study will be given in Phase II study.
Interventions: intervention 1: Lenalidomide intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Lenalidomide is a thalidomide analogue with immunomodulatory, anti-angiogenic, and antineoplastic effects. It is administered as a pill taken orally. It has completed phase III study evaluation and has FDA indications for use in certain patients with multiple myeloma, myelodysplastic syndrome, and mantle cell lymphoma. intervention 2: Pembrolizumab is a humanized IgG4 monoclonal antibody which targets the PD-1 receptor, thus inhibiting the interaction between PD-1 and its ligands, PD-L1 and PD-L2 respectively. It is administered as an IV infusion. This drug has several studies in patients with solid tumors and currently has an FDA indication for use in patients with melanoma and non-small cell lung cancer.

Protocol documents:
Prot_SAP_000.pdf: 
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Copyright© 2016 Fox Chase Cancer Center® Office of Clinical Research.  All rights reserved. 
Version Date 12/9/2016 
 
 
A Phase I Study of Lenalidomide plus Pembrolizumab in Patients with Relapsed and/or 
Refractory Solid Tumors with Phase II Expansion in Non-Small Cell Lung Cancer 
 
Supported by Merck and Celgene 
 
Sponsor Investigator: 
Hossein Borghaei, DO 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia PA, 19111 
Phone: 215-214-4297 
Fax: 215-728-3639 
Email: Hossein.Borghaei@fccc.edu 
 
Co-Investigators: 
 
 
Fox Chase Cancer Center 
James L. Godwin, MD 
Anthony J. Olszanski, MD 
Jessica Bauman, MD 
Kerry Campbell, Ph.D. 
 
 
 
 
 
 
James Cancer Center 
Gregory Otterson, MD 
James Cancer Center  
Ohio State University 
B450 Starling Loving Hall 
320 W.10th Avenue 
 
Columbus, OH 43210 
Phone: 614-293-9424 
Fax: 614-293-4372 
Email: otterson.1@osu.edu 
 
Lineberger Cancer Center 
Jared Weiss, MD 
School of Medicine 
UNC- Chapel Hill 
3115 Physicians Office Building 
170 Manning Drive  
Chapel Hill, NC 27599 
Phone: 919-966-4431 
Fax: 919-966-6735 
Email: jared_weiss@med.unc.edu 
 
 
 
 
 
 
 
 
 


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Statistician: 
 
 
 
Eric Ross, Ph.D. 
Fox Chase Cancer Center 
333 Cottman Avenue 
Philadelphia PA, 19111 
Phone: 215-728-2891 
Email: Eric.Ross@fccc.edu 
 
 
 
 
 
 
 
Protocol Version Date:   10/07/2016 
Amendment 1: 
       12/9/2016 
 
 
 
 


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Table of Contents 
Table of Contents ______________________________________________________________ 3 
Phase I Schema _______________________________________________________________ 6 
Phase II Schema _______________________________________________________________ 7 
Study Flowchart _______________________________________________________________ 8 
1.0 
Introduction ______________________________________________________________ 9 
1.1 
Study Disease _________________________________________________________ 9 
1.2 
Non-Small Cell Lung Cancer ____________________________________________ 9 
1.3 
Agents under Investigation ____________________________________________ 10 
1.4 
Background __________________________________________________________ 10 
1.5 
Rationale _____________________________________________________________ 13 
2.0 
Objectives ______________________________________________________________ 14 
2.1 
Primary Objective _____________________________________________________ 14 
2.2 
Secondary Objectives _________________________________________________ 14 
3.0 
Study Plan ______________________________________________________________ 14 
3.1 
Description of Study Design, Population and Duration of Study Therapy __ 14 
4.0 
Patient Selection Inclusion & Exclusion ___________________________________ 16 
4.1 
Inclusion Criteria ______________________________________________________ 16 
4.2 
Exclusion Criteria _____________________________________________________ 17 
4.3 
Inclusion of Women and Minorities _____________________________________ 18 
4.4 
Pregnancy ____________________________________________________________ 18 
4.4.1 
Contraception _____________________________________________________________ 19 
4.4.2 
Lenalidomide pregnancy prevention plan _____________________________________ 21 
4.5 
Patient Registration ___________________________________________________ 21 
5.0 
Treatment Plan __________________________________________________________ 22 
5.1 
Treatment Administration ______________________________________________ 22 
5.2 
Concomitant Medications, Supportive Care, Excluded Therapies and Restrictions
 
22 
5.2.1 
Prohibited during the study: _________________________________________________ 23 
5.3 
Duration of Therapy ___________________________________________________ 23 
5.4 
Duration of Follow up __________________________________________________ 24 
5.5 
DLT Definition_________________________________________________________ 24 
6.0 
Dose Modifications ______________________________________________________ 24 
6.1 
General Principles _____________________________________________________ 24 
6.2 
Dose Level Adjustment Table __________________________________________ 24 


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6.3 
Specific Toxicities and Modifications ___________________________________ 25 
6.3.1 
Dose modifications for lenalidomide __________________________________________ 25 
6.3.2 
Dose Modifications for Pembrolizumab _______________________________________ 28 
6.4 
Toxicities and AE management. ________________________________________ 29 
7.0 
Study Agent Information _________________________________________________ 31 
7.1 
Lenalidomide Information ______________________________________________ 31 
7.1.1 
Formulation _______________________________________________________________ 31 
7.1.2 
Availability ________________________________________________________________ 32 
7.1.3 
Solution preparation _______________________________________________________ 32 
7.1.4 
Storage requirements ______________________________________________________ 32 
7.1.5 
Stability ___________________________________________________________________ 32 
7.1.6 
Route of administration _____________________________________________________ 32 
7.2 
Pembrolizumab Information ____________________________________________ 32 
7.2.1 
Formulation _______________________________________________________________ 32 
7.2.2 
Availability ________________________________________________________________ 33 
7.2.3 
Solution preparation _______________________________________________________ 33 
7.2.4 
Storage requirements ______________________________________________________ 33 
7.2.5 
Stability ___________________________________________________________________ 33 
7.2.6 
Route of administration _____________________________________________________ 33 
7.3 
Drug Ordering, Storage and Handling ___________________________________ 33 
7.4 
Destruction of Drug ___________________________________________________ 33 
7.5 
Records to be kept at Site; Dispensing and Accountability _______________ 33 
8.0 
Correlative / Special Studies ______________________________________________ 34 
9.0 
Study Calendar __________________________________________________________ 35 
10.0 Adverse Events & Events of Clinical Interest _______________________________ 37 
10.1 Definitions ____________________________________________________________ 37 
10.1.1 Severity Rating ____________________________________________________________ 37 
10.1.2 Attribution/Relationship to study drug ________________________________________ 37 
10.1.3 Expectedness _____________________________________________________________ 37 
10.1.4 Events of Clinical Interest ___________________________________________________ 38 
10.2 Recording and Reporting Responsibilities ______________________________ 38 
10.2.1 Investigative site recording responsibilities: ___________________________________ 38 
10.2.2 Investigative site reporting responsibilities: ____________________________________ 39 
10.2.3 OCR Reporting Responsibilities: _____________________________________________ 39 
10.2.4 OCR Reporting to Merck ___________________________________________________ 40 
10.3 Pregnancy ____________________________________________________________ 42 
11.0 Measures of Effect _______________________________________________________ 43 
11.1 Definitions ____________________________________________________________ 43 
11.2 Disease Parameters ___________________________________________________ 43 
11.3 Methods for Evaluation of Measurable Disease __________________________ 44 
11.4 Response Criteria _____________________________________________________ 46 
11.4.1 Evaluation of Target Lesions ________________________________________________ 46 


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11.4.2 Evaluation of Non-Target Lesions____________________________________________ 46 
11.4.3 Evaluation of Best Overall Response _________________________________________ 47 
11.5 Duration of Response _________________________________________________ 48 
11.6 Progression-Free Survival _____________________________________________ 48 
12.0 Statistical Considerations ________________________________________________ 48 
12.1 Study Design/Endpoints _______________________________________________ 48 
12.2 Toxicity _______________________________________________________________ 49 
12.3 Sample Size/Accrual Rate ______________________________________________ 49 
12.4 Stratification Factors __________________________________________________ 49 
12.5 Analysis of Secondary Endpoints ______________________________________ 49 
12.6 Reporting and Exclusions ______________________________________________ 49 
12.6.1 Evaluation of toxicity _______________________________________________________ 49 
12.6.2 Evaluation of response _____________________________________________________ 50 
13.0 Data and Safety Monitoring Plan __________________________________________ 50 
13.1 Monitoring Plan _______________________________________________________ 50 
13.2 Data Safety Monitoring Committee ______________________________________ 50 
14.0 Administrative ___________________________________________________________ 50 
14.1 Data Reporting ________________________________________________________ 51 
14.2 Retention of Records __________________________________________________ 51 
14.3 Study Agents _________________________________________________________ 51 
14.4 Informed Consent _____________________________________________________ 51 
15.0 References ______________________________________________________________ 52 
16.0 Appendix A: Lenalidomide Pregnancy Prevention Plan _____________________ 55 
 
 
 


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Phase I Schema 
 
 
 
 
 
 
 
 
 
 
 
Population: Patients must have a histologically or cytologically 
confirmed metastatic solid tumor malignancy and have 
completed no more than two lines of prior therapies. 
6-18 patients total 
(Three cohorts of 3 patients per cohort) 
 
Treatment (21 days per cycle): 
Pembrolizumab 200 mg administered day 1 of each cycle in each 
Cohort  
+ 
Cohort 1: (3 patients) 
Lenalidomide 10 mg PO daily days 1 – 14; if no DLT then: 
 
Cohort 2: (3 patients) 
Lenalidomide 15 mg, PO daily days 1- 14, if no DLT then: 
 
Cohort 3: (3 patients) 
Lenalidomide 20 mg, PO daily, days 1-14 
Disease Assessment 
Evaluation every two cycles (+/-3 days days) with CT imaging 
For all cohorts: continue treatment 
until: 
Disease progression 
Unacceptable toxicity 
Patient preference 
Two years of therapy 


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Phase II Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Population: Patients with a diagnosis of non-small cell lung cancer, regardless of 
histology after progression through one line of treatment with an appropriate 
regimen (platinum doublet or targeted therapy). 
 
A two stage design will be employed: 13 patients initially, with a plan to add 13 more 
if at least 7 of the initial 13 patients are progression-free (PF) at 10 weeks after 
starting treatment.  
Treatment (21 days per cycle): 
 
Pembrolizumab 200 mg administered day 1 of every 21-day cycle 
 
Lenalidomide at a dose determined by phase I study administered orally every day 
from day 1 – day 14 of every 21 day cycle 
Disease Assessment 
Evaluation every two cycles (+/-3 
days days) with CT imaging 
Continue Treatment Until: 
Disease progression 
Unacceptable toxicity 
Patient preference 
Two years of therapy 


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Study Flowchart 
 
 


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1.0 Introduction 
1.1 Study Disease 
The prognosis for patients with relapsed and/or refractory metastatic solid tumor 
malignancies remains generally poor, and new drugs and drug combinations are needed for 
this group of patients. Ideally, these drugs and combinations will have a limited side effect 
profile. With the recent development of novel immunotherapeutic agents, such as the anti-
programmed death 1 (PD-1) antibodies, new combinations are possible (i.e. combining new 
agents with older therapies). We propose to explore a novel drug combination for patients 
with relapsed and/or refractory advanced solid tumors, with a plan to pursue further study in 
an expansion phase II cohort in patients with advanced non-small cell lung cancer (NSCLC). 
We have chosen NSCLC based on recent data showing significant responses to anti-PD1 
antibody therapies.1,2 
 
1.2 Non-Small Cell Lung Cancer 
Lung cancer is affecting an ever increasing number of patients, and remains one of the 
world’s leading causes of cancer-related deaths. There have been many developments in the 
management of lung cancer, especially in Non-Small Cell Lung Cancer (NSCLC).  These 
new treatments take into account the histology and molecular characteristics of the tumor as 
well as patient characteristics. 
 
The management of NSCLC has historically relied on the use of cytotoxic chemotherapy and 
responses have been modest. Advances in our understanding of the tumor biology, along 
with identification of specific molecular alterations, have allowed a more personalized 
approach for treatment of some patients with this disease. 
 
In advanced NSCLC, use of platinum doublets has been the accepted standard of care for 
many years. Studies such as ECOG 1594 and SWOG 9509 compared several platinum based 
doublet regimens and found them to be equally effective, with minor differences in toxicity 
profile.3,4 The median progression free survival has remained at approximately five months.5  
None of these studies reported a particular advantage in any of the subgroups analyzed with 
the exception of pemetrexed-based treatment in non-squamous histology where survival 
appears to be better.5  
 
For a subset of patients with molecularly defined disease, such as those with an activating 
EGFR mutation or an EML4-ALK translocation, we now have effective first, second and 
third line treatment options.6 It appears that in this small sub-population emergence of newer 
drugs and the ability to define the resistance mechanisms and the availability of specific 
agents for these resistance mechanisms has led to an improvement in the overall survival of 
these patients.7  
 
For patients with advanced lung cancer who do not have a molecularly defined aberration, 
the activity of immune checkpoint inhibitors has been welcomed news. A number of 
antibodies targeting either the programed death-1 (PD-1) pathway or the cytotoxic T 
lymphocyte antigen-4 (CTLA-4) have captured the attention of many in the field. Nivolumab 
(BMS), an anti PD-1 antibody, is approved for treatment of patients with squamous cell 


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carcinoma of the lung after disease progression following treatment with a platinum doublet.   
This approval is based on the superior survival of this agent as compared with standard of 
care docetaxel in this population in a randomized phase III trial.2 A similar study recently 
reported a survival benefit for nivolumab over docetaxel in patients with non-squamous 
histology and led to FDA approval of this agent for the non-squamous patient population as 
well.8 
 
Pembrolizumab (Merck) is also an anti PD-1 antibody with significant activity in NSCLC as 
demonstrated by a large single arm study that examined several different dose ranges and 
schedules of this agent.1 This study reported data on 495 patients treated with 
pembrolizumab. In addition to evaluating for safety and side effect profile, the investigators 
also sought to define separate cohorts using a PD-L1 assay as a biomarker to predict drug 
efficacy. This study revealed an overall response rate (ORR) of 19.4%, with 84.4% of 
responding patients without disease progression at the time of data analysis. Median duration 
of response was 12.4 months in all patients and median overall survival (OS) was 12.0 
months (16.2 months for previously untreated patients). When the patients were divided into 
groups based on degree of PD-L1 staining positivity in tumor samples – PD-L1 < 1%, PD-L1 
1-49%, PD-L1 > 50% - the degree of PD-L1 positivity correlated strongly with response. 
Patients in the highest expressing group of PD-L1 (50% or greater) had a response rate of 
45.2%, and patients with no prior treatment had the best response ratesand longest duration 
of response. These exciting results have led to many further trials evaluating the role of 
pembrolizumab in patients with NSCLC, including combination therapy trials with many 
different classes of agents.  On October 2, 2015, the FDA granted regulatory approval for this 
agent in patients with PD-L1 expressing NSCLC regardless of histology.   
 
1.3 Agents under Investigation 
Pembrolizumab is a humanized IgG4 monoclonal antibody which targets the PD-1 receptor, 
thus inhibiting the interaction between PD-1 and its ligands, PD-L1 and PD-L2 respectively.  
It is administered as an IV infusion. This drug has several studies in patients with solid 
tumors and currently has an FDA indication for use in patients with melanoma and non-small 
cell lung cancer.  
 
Lenalidomide is a thalidomide analogue with immunomodulatory, anti-angiogenic, and 
antineoplastic effects. It is administered as a pill taken orally. It has completed phase III 
study evaluation and has FDA indications for use in certain patients with multiple myeloma, 
myelodysplastic syndrome, and mantle cell lymphoma.  
 
1.4 Background 
Considerable excitement has developed in recent years regarding the use of immune 
checkpoint blockade agents for the treatment of patients with solid and hematologic 
malignancies.9,10 The concept that tumors evade immune surveillance through a variety of 
mechanisms, and that activating the immune system can lead to tumor regression in a variety 
of tumor types has been known for decades.11 The hypothesis which led to the development 
of immune checkpoint blockade agents was that inhibition of the biologic pathways which 
serve to dampen immune response (serving as “checkpoints” to ensure immune homeostasis 
and preventing deleterious autoimmune effects), would lead to uninhibited immune 


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activation and subsequent anti-tumor effects. The first immune checkpoint receptor to be 
clinically targeted was cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), a Type I 
transmembrane protein of the Ig superfamily expressed on activated T cells which helps to 
regulate immune responses and prevent autoimmune reactions. 12,13  The anti-CTLA-4 
monoclonal antibody (mAb) ipilimumab (Yervoy; Bristol-Myers Squibb, NJ) was developed 
due to promising preclinical studies, and became the first FDA approved checkpoint 
blockade agent in March 2011, based on results of two phase III studies in advanced 
melanoma which showed an improvement in overall survival (OS).14,15 
 
The second immune checkpoint pathway to be clinically targeted was programmed cell death 
protein 1 (PD-1) and its associated ligands (PD-L1 and PD-L2). PD-1, like CTLA-4, is also a 
Type I transmembrane protein of the Ig superfamily, but it is expressed on a wider variety of 
cells including T cells, NK cells and B cells among others. The ligands for PD-1 (e.g. PD-L1 
and PD-L2) are expressed on a wide variety of cells, including non-hematopoietic cells, and 
expression can be upregulated based on various stimuli. The primary function of PD-1 is 
believed to be inhibition of T cell effector responses within peripheral tissues (including 
tumors), as opposed to CTLA-4 which primarily regulates early T cell activation phases 
(primarily in lymph tissue).16,17 One of the first anti-PD-1 agents to enter clinical trials was 
nivolumab (Opdivo; Bristol-Myers Squibb, NJ), a fully human IgG4 mAb targeted to PD-1; 
phase I trials with this drug revealed responses not only in the typical immune-responsive 
malignancies (known to respond to treatment with IL-2 and interferon-a) such as melanoma 
and renal cell carcinoma (RCC), but also in non-small cell lung cancer (NSCLC).18,19 
Subsequent studies of nivolumab in advanced melanoma led to accelerated FDA approval in 
December 2014.20,21 In March 2015, nivolumab was approved for use in the second-line 
setting in patients with squamous cell NSCLC; nivolumab subsequently  obtained approval 
for use in the second line setting for patients with non-squamous NSCLC in October 2015. 
Pembrolizumab (Keytruda; Merck, NJ) is a humanized IgG4 mAb targeted to PD1 which has 
also been studied in a variety of tumor types with impressive clinical responses; the most 
mature data are in advanced melanoma and pembrolizumab received FDA approval for 
treatment of this disease in September 2014.22,23 This agent received FDA approval for 
treatment of PD-L1 expressing NSCLC regardless of histology in the second line setting on 
October 2, 2015. 
 
Though the response rate to treatment with these checkpoint blockade agents in the setting of 
advanced solid tumor malignancies is encouraging, even more exciting is the durability of 
some of the responses, including some which are ongoing for years.21 Though these three 
drugs (ipilimumab, nivolumab, pembrolizumab) are the only checkpoint blockade agents 
currently FDA approved in the United States, many more are in the development pipeline.24 
Based on the efficacy of checkpoint blockade agents in other tumor types (most mature data 
in RCC, NSCLC and melanoma, encouraging early data in bladder cancer, breast cancer, 
Hodgkin lymphoma, among others) other FDA approved indications are expected in 2016 
and 2017.  
 
In contrast to these novel immune activating drugs, thalidomide (Thalomid, Celgene, NJ), an 
agent with immunomodulatory properties, was being used and investigated in the 1940s as an 
antiemetic and sedative. After largely disappearing following the tragic era of its use as an 


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antiemetic in pregnant women leading to teratogenicity (dysmelia), this drug and related 
agents have returned to clinical medicine within the past ten years.  This class of drugs – the 
immunomodulatory agents (IMiDs), developed by Celgene - include thalidomide, 
lenalidomide (Revlimid, Celgene, NJ) and pomalidomide (Pomalyst, Celgene, NJ); have 
received regulatory approval by the FDA for treatment of a variety of hematologic 
malignancies, including multiple myeloma (all three agents), myelodysplastic syndrome and 
mantle cell lymphoma (lenalidomide) and erythema nodusum leprosum (thalidomide).  
 
The IMiDs have multiple mechanisms of action, including stimulation of T cell activation, 
augmentation of cytotoxic T and NK effector cell functions, anti-angiogenic properties, and 
epigenetic alterations, among others.25,26 The ability of the IMiDs to activate T cells – 
cytotoxic T cells and T helper cells – by utilizing the B7/CD28 pathway is intriguing, as this 
pathway involves the checkpoint receptors discussed above; one study specifically indicates 
the ability of an IMiD to overcome CTLA-4 mediated inhibition.27 Lenalidomide has been 
studied as a phase I single agent and in combination with chemotherapy in many different 
solid tumor types, including NSCLC, with multiple responses noted.28 However, thus far 
there have been no clinical studies exploring the combination of a checkpoint blockade agent 
with an IMiD in solid tumor malignancies.  
 
Lenalidomide has been shown to enhance CD4 and CD8 T cell co-stimulation, and to induce 
T cell proliferation much more potently than its precursor drug thalidomide.29 Part of this 
process includes increased release of the pro-inflammatory cytokine interleukin-2 (IL-2) by T 
cells. Recent research suggests a mechanism for this change in the inflammatory milieu: 
lenalidomide regulates ubiquitination and degradation of two key lymphoid transcription 
factors, IKZF1 and IKZF3. IKZF3 binds to the gene promoter of IL-2 and represses the 
transcription of IL-2 in T-cells, thus a lenalidomide-induced decrease in IKZF3 levels yields 
downstream increased production of IL-2, with its subsequent immunomodulatory effects.30 
Lenalidomide also inhibits the function of T regulatory cells (Treg), which are known to play 
a key role in helping tumors evade immune evasion by increasing tolerance and 
downregulating immune activation.31 
 
Given that both of these classes of drugs – IMiDs and anti-PD1 antibodies - induce anti-
tumor effects through T cell activation, utilizing different mechanisms of action, it is 
reasonable to propose that combining a drug from each class together in one treatment 
regimen could have significant anti-tumor effect, perhaps greater than either might have 
alone. We propose to open a phase I trial for patients with advanced solid tumor 
malignancies to explore the maximum tolerated dose (MTD) of an IMiD (lenalidomide) in 
combination with a fixed and approved dose of an anti-PD1 agent (pembrolizumab), 
followed by an expansion cohort phase II trial in non-small cell lung cancer.  We prefer to 
study an anti-PD-1 agent versus an anti-CTLA-4 agent given the wider range of tumor types 
responsive to anti-PD-1 therapy and because the anti-PD-1 drugs are typically better tolerated 
than the anti-CTLA-4 drugs. Patients with advanced, refractory solid tumors need better 
therapeutic options, and we hope that utilizing the above proposed combination 
immunotherapy regimen may offer hope for meaningful and durable responses.  
 
It is important to emphasize that due to a lack of an appropriate mouse model, it is not 


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possible to test this combination in the preclinical setting. Moreover, the safety profile of 
both agents is well known. The dose modifications schema for lenalidomide is well 
established and this agent has been given, either alone or in combination with other drugs, 
safely and effectively to thousands of patients around the world.  
 
An abstract presented at the most recent American Society of Hematology Annual Meeting 
in December 2015 reported data from a phase I study of pembrolizumab in combination with 
lenalidomide and dexamethasone for relapsed/refractory multiple myeloma.32  Data from 17 
patients who were treated during the dose determination and dose confirmation phase was 
presented. Sixteen patients experienced at least one AE of any grade, and 10 patients 
experienced at least one AE of grade 3 or 4. However, no deaths or treatment discontinuation 
for toxicity was noted. The most frequently noted AEs (> 25%) were thrombocytopenia 
(47%), neutropenia (41%), and fatigue (29%). Of note, this was a heavily pretreated 
population (53% had ≥3 treatments, and 41% had IMiD-refractory disease) and the therapy 
combination was well-tolerated. No thromboembolic events were reported. The MTD/MAD 
was defined as pembrolizumab 200 mg fixed dose in combination with lenalidomide 25 mg 
and low-dose dexamethasone 40 mg. Objective response rate was 76%. This data from this 
study suggests that this combination of drugs is well tolerated, and will likely be tolerated in 
the context of patients with advanced solid tumors, as we propose in this trial.  
 
1.5 Rationale 
It has become clear in recent years that drugs aimed at enhancing and modifying immune 
responses to tumor cells will be an essential and growing component of oncology’s 
armamentarium. There is data to show that anti-PD-1 antibodies can have impressive anti-
tumor effects as single agents, in a wide variety of primary cancers. Future studies will seek 
to investigate the optimal therapeutic timing of these agents (e.g. first-line versus nth line) as 
well as novel drug combinations which will seek to augment efficacy. There are currently 
combination trials involving pembrolizumab and at least nine different classes of drugs. 
However, there has been no study using pembrolizumab in combination with an IMiD, a 
class of drugs which has pleotropic immunomodulatory effects which may synergize with the 
effect of an anti-PD-1 agent, in solid tumors. Activating the anti-tumor effects of T cells 
utilizing the multiple pathways of both pembrolizumab and lenalidomide is an endeavor 
which merits investigation.  
 
Our hypothesis is that this combination will be well-tolerated, without significant toxicities 
or adverse events. Numerous studies have found the anti-PD-1 agents to be well-tolerated, 
and lenalidomide has also been shown to have relatively minimal side effects.28,33 We expect 
that we will reach dose level 2 of lenalidomide (20 mg) without experiencing dose-limiting 
toxicities (DLT). We intend to capitalize on the immune-modulatory effects of lenalidomide 
in combination with pembrolizumab. Since the population enrolled in this trial are pre-treated 
with standard agents, we would like to minimize the potential myelosuppresive effects of this 
agent. We also believe that we can achieve maximal immune modulation with doses selected. 
Therefore, we did not incorporate higher doses of lenalidomide in this trial.  Toxicity grading 
will be recorded using the NCI Common Terminology Criteria for Adverse Events (CTCAE) 
v.4.0. Doses for lenalidomide were selected on the basis of previously published early phase 
trials for patients with solid tumor malignancies, as well as the approved dosing levels for 


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hematologic malignancies (e.g. myeloma, MDS).28 The fixed dose of pembrolizumab was 
determined based on prior studies, including a recently published study in patients with 
NSCLC.1  
 
The primary endpoint for the phase I component of this protocol will be determining the 
maximum tolerated dose (MTD) of lenalidomide in combination with pembrolizumab.  
 
The primary endpoint for the phase II component of this protocol will be determining 
efficacy as measured by progression free survival (PFS), and our hypothesis is that this novel 
drug combination will improve PFS as described below.  
 
2.0 Objectives 
2.1 Primary Objective 
Phase I: To determine the safety, tolerability, and the maximum tolerated dose (MTD) of 
lenalidomide in combination with a fixed dose of pembrolizumab in subjects with relapsed 
and/or refractory solid tumors.  
 
Phase II (in NSCLC): To determine efficacy as measured by progression free survival (PFS). 
 
2.2 Secondary Objectives  
Phase I/II: 
 
a) Assess antitumor activity of the combination as measured by objective response rate. 
 
b) Preliminary assessment of immune correlates, including T and NK cell subset frequency 
and activation phenotype, cytokine profiles, and specific T and NK cell responses. 
 
c)  Assessment of PD-L1 expression and correlation with responses. 
 
d) Explore potential to overcome resistance in patients previously treated with an anti-PD1 
antibody. 
 
3.0 Study Plan 
3.1 Description of Study Design, Population and Duration of Study Therapy 
For the phase I component of our trial we will utilize a classic 3 + 3 dose escalation design, 
with a fixed dose of pembrolizumab and an escalating dose of the lenalidomide (see Schema 
above). The patient population will all have histologically confirmed advanced solid tumor 
malignancy with at least one lesion that is measurable by RECIST 1.1 criteria, ECOG 
performance status of 0-1, either one or two lines of prior therapy, and adequate liver, kidney 
and bone marrow function as described in section 4.0. Previous surgery, adjuvant 
chemotherapy and or radiation therapy will be allowed. The baseline pathologic specimen 
will be assessed for PD-L1 staining. Baseline blood samples will be collected for 
immunologic correlates prior to treatment on Day 1 of Cycle 1 and post treatment at 2, 4, 24 
hours.  Samples will also be collected prior to treatment on Day 1 of Cycle 2, and at time of 


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progression. Baseline CT scan of the chest and abdomen will be obtained within 30 days 
prior to the initiation of cycle 1. CT scan with contrast or MRI with contrast of the brain will 
also be obtained within 30 days prior to the initiation of cycle 1. 
 
The study will plan to enroll 3 patients in an initial cohort, to receive the dose level 1 of 
lenalidomide (10 mg PO) on days 1-14 of a 21-day cycle, and  pembrolizumab (200 mg IV) 
on day 1. Patients will be evaluated for toxicities after initiation of treatment. If there are no 
DLTs for the initial 3 patients after one cycle, the next dosing cohort will open, with another 
3 patients. Similarly, if the second cohort of patients receives the dose level 2 of 
lenalidomide (15 mg) for one cycle without DLT, then the third and final cohort will open. 
When the third cohort testing the dose level 3 of lenalidomide (20 mg) has completed one 
cycle, the phase I component of the trial will be completed. Standard phase I, 3 + 3 design 
rules will be utilized as follows: if 1 out of 3 patients experiences a DLT at certain dose level, 
then 3 more patients will be enrolled at the same level. If 2 out of 6 patients experience DLT 
at a certain dose level, 3 additional patients are added at the next lower level. Dose reduction 
is continued until at most 1 of 6 patients experiences DLT. The highest level with at most 1 
of 6 patients DLT will be declared MTD. If no dose level achieves this criterion the trial will 
be discontinued for excess toxicity. 
 
At Fox Chase Cancer Center, we see roughly 10,000 new patients annually, and enroll 
approximately 200 patients annually, on phase I trials. 6-18 patients will be enrolled to 
complete the phase I component of this protocol, and we should be able to accrue this 
number within 6 months (1-2 patients per month). Patients will continue to be followed every 
21 days on the first day of each new cycle for the first 12 months on this protocol. Patients 
who remain on study after the initial 12 months will be evaluated once every 2 cycles until 
disease progression, unacceptable toxicity or withdrawal of consent.  
 
The phase II component of this trial will utilize a two stage design as described in the 
statistical section, initially enrolling 13 patients, followed by 13 more patients if the early 
stopping criteria are not met (See statistics section). This population will include patients 
with histologically confirmed diagnoses of non-small cell lung carcinoma, regardless of 
histologic subtype; who have completed one line of standard therapy. Previous surgery, 
adjuvant chemotherapy and or radiation therapy will be allowed. Patients with molecular 
targets (EGFR, ALK, ROS1) who have progressed on targeted agents and are not eligible for 
other treatments or trials specific for this population will be allowed to participate. A pre-
treatment (archival) and fresh tumor sample will be needed for participation in trial. PD-L1 
expression levels in both samples will be determined to assess the role of chemotherapy on 
expression level and pattern of this biomarker. Baseline blood samples will be collected for 
immunologic correlates prior to treatment on Day 1 of Cycle 1 and post treatment at 2, 4, 24 
hours.  Samples will also be collected prior to treatment on Day 1 of Cycle 2, and at time of 
progression. Baseline CT scan of the chest and abdomen will be obtained within 30 days 
prior to the initiation of cycle 1. CT scan with contrast or MRI with contrast of the brain will 
also be obtained within 30 days prior to the initiation of cycle 1. Time to progression will be 
measured with disease imaging following every 2 cycles of therapy with a three-day window 
(+ or -).  Patients will continue treatment until disease progression or unacceptable toxicity or 
two years of therapy.  Overall survival will be assessed every 3 months during long term 


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follow up. Accrual of the required 26 patients will likely take 12 months.    
 
As another exploratory analysis, we intend to treat 10 additional patients with prior treatment 
with any of the anti PD-1/PD-L1 antibodies and subsequent progression on this protocol. The 
intent is to explore the possibility of overcoming PD-1 axis resistance through inhibition of 
Treg activity.  
 
4.0 Patient Selection Inclusion & Exclusion 
4.1 Inclusion Criteria   
4.1.1 Patients must have a histologically or cytologically confirmed metastatic solid 
tumor malignancy for the phase I component. The phase II component will 
require patients to have histologically or cytologically confirmed non-small 
cell lung carcinoma regardless of histology. 
4.1.2 Patients must have measurable disease, defined as at least one lesion that can 
be accurately measured in at least one dimension in accordance with RECIST 
criteria v. 1.1 as described in detail in section 11.0. 
4.1.3 For participation in the Phase II portion, patients must have completed at 
least one line of prior therapy. 
 
For participation in the Phase I portion, patients must have completed 
either one or two lines of prior therapy. 
 
Treatment on this protocol may begin as long as the patient has recovered 
from toxicities of prior therapy at the discretion of the treating physician. 
Patients with NSCLC harboring an EGFR, ALK or ROS-1 alteration must 
have progressed through at least one prior therapy with appropriate 
molecularly targeted agents.  
4.1.4 Age > 18 years. 
4.1.5 ECOG performance status 0 or 1. 
4.1.6 Patients must have normal organ and marrow function as defined below: 
Absolute neutrophil count 
> 1,500/mcL 
Hemoglobin 
≥ 9.0 mg/ml 
Platelets  
> 100,000/mcL 
Total bilirubin 
within normal institutional limits 
AST/ALT (SGOT/SGPT) 
< 2 times institutional normal limits, or up to 5 times 
institutional normal limits if the patient has liver metastases 
Creatinine OR  
Creatinine clearance 
within normal institutional limits OR > 60 Ml/min/1.73 m2 
for patients with creatinine levels above institutional normal 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 


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Activated Partial Thromboplastin 
Time (aPTT)  
 
≤1.5 X ULN unless subject is receiving anticoagulant 
therapy as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
 
4.1.7 Ability to understand and willingness to sign a written informed consent and 
HIPAA consent document. 
4.1.8 Palliative radiation for treatment of painful bone metastasis, control of 
hemoptysis or treatment of small asymptomatic brain metastasis that become 
symptomatic during on protocol treatment is allowed. Protocol treatment will 
be delayed until recovery from radiation at the discretion of the treating 
physician. 
4.1.9 A core tumor biopsy obtained after progression on the last treatment must be 
available at study entry for the phase II portion of the study. Any available 
archival tissue (for both phase I and II) will also be collected. 
4.1.10 Female subject of childbearing potential must have a negative serum 
pregnancy 10-14 days prior to registration, and again within 24 hours prior to 
the first dose of Lenalidomide,   
4.1.11 All study participants must be registered into the mandatory Revlimid REMS® 
program, and be willing and able to comply with the requirements of the 
REMS® program. 
4.1.12 Female subject of childbearing potential must have a negative serum 
pregnancy 10-14 days prior to registration, and again within 24 hours prior to 
the first dose of lenalidomide, Females of reproductive potential must adhere 
to the scheduled pregnancy testing as required in the Revlimid REMS® 
program. 
4.1.13 Female subjects of childbearing potential must be willing to use an adequate 
method of contraception as outlined in Section 4.4.1 – Contraception, for the 
course of the study through 120 days after the last dose of study medication. 
4.1.14 Male subjects of childbearing potential must agree to use an adequate method 
of contraception as outlined in Section 4.4.1- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study 
therapy. 
4.1.15 Ten patients with a diagnosis of NSCLC who have disease progression per 
investigator’s assessment who are on anti PD-1 or PD-L1 therapies will be 
allowed to enroll in the phase II part of this study but must be switched to 
treatment per this protocol.  
 
4.2 Exclusion Criteria 
4.2.1 Patients who have had chemotherapy or radiotherapy within14 days prior to 
entering the study. Patients may not be currently receiving any other 
investigational agents or immunomodulatory agents (e.g. ipilimumab). 


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Patients treated with prior PD-1 or PD-L1 directed therapies are ineligible for 
the phase I portion. 
4.2.2 Patients who, at the discretion of the treating physician, have not recovered 
from adverse events due to agents administered earlier. 
4.2.3 Patients with active autoimmune disease that has required systemic treatment 
in the past 2 years (i.e. with use of disease modifying agents, corticosteroids 
or immunosuppressive drugs). Replacement therapy (eg. thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
4.2.4 Patients with untreated symptomatic brain metastases. Patients with treated 
brain metastases will be allowed if brain imaging obtained within 30 days of 
trial enrollment reveals stable disease. Patients with small asymptomatic brain 
metastasis are allowed to enroll. Patients on steroids doses higher than 10 mg 
of prednisone (or its equivalent) are excluded. 
4.2.5 Patients with interstitial lung disease or active, noninfectious pneumonitis. 
4.2.6 Patient who have received a live vaccine within 30 days prior to Cycle 1 Day 
1. 
4.2.7 Uncontrolled intercurrent illness including, but not limited to, ongoing or 
active infection (including HIV, hepatitis B, hepatitis C), symptomatic 
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, 
cirrhosis, or psychiatric illness/social situations that would limit compliance 
with study requirements. 
4.2.8 Patients with known hypersensitivity to thalidomide or lenalidomide or 
pomalidomide. 
4.2.9 Patients with peripheral neuropathy of grade ≥3. Patients with painful grade 2 
neuropathy are also excluded.  
4.2.10 Pregnant or breast-feeding. Refer to section 4.4 for further detail. 
 
4.3 Inclusion of Women and Minorities 
Men and women, regardless of race, ethnic group or sexual orientation are eligible for this 
study.   
 
4.4 Pregnancy 
Lenalidomide is an analogue of thalidomide, which is an agent known to have significant 
teratogenic effects; for this reason, women of child-bearing potential (WOCBP) and men 
must agree to use adequate contraception (hormonal or barrier method of birth control; 
abstinence) prior to study entry, for the duration of treatment, and for at least 120 days after 
the completion of treatment.  Should a woman become pregnant or suspect she is pregnant 
while participating in this study, she must inform her treating physician immediately. 
 
Prior to study enrollment, WOBCP must be advised of the importance of avoiding pregnancy 


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during trial participation and the potential risk factors for an unintentional pregnancy.  In 
additional, men enrolled on this study should understand the risks to any sexual partner of 
childbearing potential. 
 
All WOCBP must have two negative pregnancy tests - within 10-14 days prior to receiving 
the first dose of Lenalidomide, and within 24 hours prior to the first dose of Lenalidomide.  If 
the pregnancy test is positive, the patient must not receive protocol treatment and must not be 
enrolled in the study. 
 
WOCBP is defined as follows: Any female who has experienced menarche and who has not 
undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or a 
bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea > 12 consecutive 
months, or women on hormone replacement therapy (HRT) with documented plasma follicle-
stimulating hormone (FSH) level > 35 mIU/ml).  Even women who are using oral, implanted, 
or injectable contraceptive hormones or mechanical products (diaphragm, condoms, 
spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g. 
vasectomy), should be considered to be WOCBP. 
 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported within 24 hours to the sponsor. 
The sponsor will report this outcome, within 24 hours, to Merck and Celgene if the outcome 
is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling 
or life-threatening complication to the mother or newborn).   
 
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner, the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor investigator, Merck, and Celgene. 
 
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor investigator.   
If a male subject impregnates his female partner, the study personnel at the site must be 
informed immediately and the pregnancy reported to the Sponsor investigator, Merck, and 
Celgene. 
 
4.4.1 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if pembrolizumab has transient adverse effects on the composition of sperm.   
 
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying 
medical condition).   
 
Female subjects will be considered of non-reproductive potential if they are either:  


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(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);  
 
OR  
 
(2) have had a hysterectomy and/or bilateral oophorectomy, or bilateral salpingectomy at 
least 6 weeks prior to screening;  
 
OR  
 
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study drug and for 120 
days after the last dose of study drug by complying with one of the following:   
 
(1) practice abstinence from heterosexual activity;  
 
OR  
 
(2) use (or have their partner use) acceptable contraception during heterosexual activity. 
 
Acceptable methods of contraception are: 
  
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
  
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or 
progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or 
subcutaneous contraceptive injection 
  
Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle 
and if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic 


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abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
 
4.4.2 Lenalidomide pregnancy prevention plan (REMS Program) 
The Pregnancy Prevention Plan (PPP) applies to all subjects receiving lenalidomide 
within a clinical trial. The following PPP documents are included: 
 
1. The Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods document provides the following information: 
 
Potential risks to the fetus associated with lenalidomide exposure 
 
Definition of female of childbearing potential (FCBP)/female not of 
childbearing potential (FNCBP) 
 
Requirements for counseling of all subjects receiving lenalidomide about 
pregnancy precautions and the potential risks of fetal exposure to 
lenalidomide 
 
Acceptable birth control methods for both female subjects of childbearing 
potential and male subjects receiving lenalidomide in the study 
 
Pregnancy testing requirements for subjects receiving lenalidomide who 
are FCBP 
 
2. The Lenalidomide Education and Counseling Guidance Document for each 
gender (female and male) must be completed and signed by a trained counselor at 
the participating clinical center prior to each dispensing of lenalidomide. A copy 
of this document must be maintained in the subject’s records for each dispense. 
 
3. The Lenalidomide Information Sheet will be given to each subject receiving 
lenalidomide. The subject must read this document prior to starting lenalidomide 
and each time the subject receives a new supply of lenalidomide. 
 
Please see the Lenalidomide Pregnancy Risk Minimization Plan in Appendix 
A for additional information 
 
4.5 Patient Registration 
Participants may be registered from 8:00 am to 4:00 pm EST excluding holidays by 
emailing the Investigator-Sponsored Research Unit (ISRU) at: 
FCCC.MONITOR@fccc.edu. Eligible participants will be entered on study centrally 
once the following items have been received by email: 
 
 Completed registration form  
 Consent and HIPAA signature pages  
 Eligibility checklist 
 Lenalidomide Education and Counseling Guidance Document (Section 3 or 4 
of Appendix A, as applicable) 
 


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Following registration, participants must begin protocol treatment within 14 calendar 
days of registration.  Issues that would cause treatment delays must be discussed with the 
Sponsor-Investigator.  If a registered participant does not receive protocol therapy 
following registration, the participant will be recorded as withdrawn from study.  The 
Study Monitor must be notified as soon as possible if a participant does not begin 
protocol treatment as scheduled. For additional registration questions, please email 
FCCC.MONITOR@fccc.edu or call (215) 728-5544. 
 
The FCCC ISRU will notify the site by email once registration is confirmed and the 
sequence number has been assigned.  Participants must be registered and have received a 
sequence number prior to the initiation of treatment.   
 
Exceptions to the current registration policies will not be permitted.  
 
5.0 Treatment Plan 
Patients will be stratified by age, primary malignancy, and performance status. Treatment will be 
administered on an outpatient basis.  Treatment will be administered as described below.  Dose 
delays and modifications should only be done following protocol guidelines described in section 
6.0.  Missed days will not be made up.  If treatment delays are > 21 days; the study therapy will 
be discontinued.   
 
5.1 Treatment Administration 
The treatment will be given on a 21-day cycle, with a dose of pembrolizumab given on day 1, 
and doses of lenalidomide given on days 1-14. The dose of pembrolizumab will be fixed at 
200 mg, whereas the dose of lenalidomide will depend upon the patient cohort as noted 
above and below. Day 1 of each cycle can be initiated +/- 3 days. 
 
 
Regimen description 
Agent 
Premedications, 
precautions 
Dose 
Route 
Schedule 
Cycle 
Length 
Pembrolizumab 
None 
200 mg in  
50 mL NSS 
IV over 30 
minutes 
Day 1 
3 weeks 
(21 days) 
Lenalidomide 
None 
10, 15, or 20 
mg  
PO 
Days 1-14 
 
Lenalidomide and steroid combination is thought to increase the chance of deep vein 
thrombosis (DVT). This risk is seen mainly in patients with hematologic malignancies. Since 
steroid dose is prohibited (except for small doses), the risk of a DVT on this protocol is 
thought to be low. The rate of this toxicity, if it occurs, will be monitored carefully. 
 
5.2 Concomitant Medications, Supportive Care, Excluded Therapies and Restrictions 
Patients should receive full supportive care therapies concomitantly during the study 


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including transfusions of blood and blood products as well as antibiotics when appropriate.  
Palliative radiation therapy is permitted for irradiating small areas of painful bony metastases 
that cannot be managed adequately using systemic or local analgesics, as long as the 
presence of these osseous metastases was recorded at baseline prior to study initiation and 
there is no definite evidence of objective disease progression at the site based on RECIST 
criteria v1.1.  Any disease progression requiring other forms of specific anti-tumor therapy 
will be cause for early discontinuation of study treatment.   
 
The following concomitant therapies warrant special attention: 
 The use of erythropoietin, colony stimulating factors (per ASCO guidelines) are 
allowed.  
 Bisphosphonates, or other approved agents for bone metastases and anti-emetics are 
allowed. 
 Non-steroidal anti-inflammatory drugs (Ibuprofen (400 mg qid) can be administered 
in patients with normal renal function (Cr clearance>80 mL/min).    
 Patients with mild to moderate renal insufficiency (Cr clearance from 45 to 79 
mL/min) should avoid taking salicylates or NSAIDs with long elimination half-lives).  
 The concomitant use of hormones or other chemotherapeutic agents will result in the 
patient’s removal from the study. An exception can be made for steroids (at doses 
higher than 10 mg of prednisone or its equivalent) administered for adrenal failure or 
as temporizing measure for symptomatic pain or breathing, rash, or at the treating 
physician’s discretion for symptom management, or hormones administered for non-
disease related conditions, e.g., insulin for diabetes.  Glucocorticosteroids may be 
used as antiemetics and megestrol acetate may be used for appetite.  
 
5.2.1 Prohibited during the study: 
Use of surgery, anti-neoplastic or anti-tumor agents not part of the study therapy, 
including chemotherapy, radiation therapy (except as stated above), immunotherapy, and 
hormonal anticancer therapy and steroid use (>10 mg prednisone or equivalent), unless as 
specified above, is not permitted while participating in this study. 
 
Use of concurrent investigational agents is not permitted. 
 
5.3 Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until one of 
the following criteria applies: 
 Disease progression 
 Intercurrent illness that prevents further administration of treatment 
 Unacceptable adverse events 
 Treatment held >21 days beyond scheduled next cycle 
 Patient becomes pregnant 
 Patient decides to withdraw from the study or 
 General or specific changes in the patient’s condition that render the patient 
unacceptable for further treatment in the judgment of the investigator 
 24 months of therapy completed with pembrolizumab 


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5.4 Duration of Follow up 
Patients will be followed every 3 months for one year after removal from study or until 
death, whichever occurs first.  Patients removed from study for unacceptable adverse events 
that are related to the study treatment will be followed until resolution or stabilization of the 
adverse events. 
 
5.5 DLT Definition 
Toxicity will be evaluated according to the NCI CTCAE, version 4.0.  These criteria are 
available online at http://ctep.cancer.gov/reporting/ctc.html. 
 
DLT will be defined as any of the following events that are considered by the Investigator to 
be related to therapy with this combination   
 Grade 4 neutropenia (ANC  500 cells/mm3) lasting more than 14 consecutive days 
 Grade 4 neutropenia associated with coincident fever (where fever is defined as an 
oral or ear temperature ≥ 38.5°C) 
 Grade 4 thrombocytopenia (plt < 25,000 cells/mm3) lasting more than 14 consecutive 
days or  platelet count less than 10,000 cells/mm3 
 Grade 3 or 4 thrombocytopenia with clinically significant bleeding. 
 Delay in the initiation of the subsequent therapy by more than 21 days (eg, one full 
cycle) due to treatment-related toxicity 
 ≥ Grade 4 non-hematological toxicity except the following: a) Grade 4 nausea or 
emesis, or both, that occurs in the absence of optimal antiemetic therapy [5-HT3 
serotonin receptor antagonist]; b) Grade 4 diarrhea that occurs in the absence of 
optimal supportive therapy 
 Grade 4 rash  
 Grade 3 fatigue lasting greater than 21 days continuously 
 Grade 4 non-hematologic toxicity 
 
 
6.0 Dose Modifications 
6.1 General Principles  
Dose modifications should be made based only on the guidelines described in this section. 
Dose reductions are permanent; there are no dose re-escalations.  Patients requiring > 2 dose 
reductions must discontinue protocol treatment.  Missed doses are not to be made up.  
Patients requiring treatment to be held > 21 days for recovery from toxicity must discontinue 
protocol treatment. 
 
6.2 Dose Level Adjustment Table 
Dose level 
Lenalidomide Dose 
Pembrolizumab Dose 
-1 dose level 
5 mg PO 
200 mg IV 
1 (Starting dose) 10 mg PO 
200 mg IV 


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2  Escalation 
15 mg PO 
200 mg IV 
3  Escalation 
20 mg PO 
200 mg IV 
 
6.3 Specific Toxicities and Modifications 
6.3.1 Dose modifications for lenalidomide 
 Stop lenalidomide for any grade 3 or 4 toxicity not noted in the tables below.  If 
the toxicity resolves to grade 2 or less in 21 days, treatment may resume as 
follows: 
 Patients with grade 4 toxicities may resume treatment on the next lower 
dose once the toxicity resolves to a grade 2 or lower within the 21 day 
window allowed. 
 Patients with first occurrence of any grade 3 toxicity may resume 
treatment at the same dose level if the toxicity has resolved to a grade 2 or 
lower within the 21 day window allowed.  
 In the event of a second grade 3 toxicity, treatment at a lower dose of 
lenalidomide may resume once toxicity resolves to a grade 2 or lower 
within the allowed 21 day window. 
 No more than two dose reductions are allowed. 
 
 


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The table below is to be used for management of lenalidomide related hematologic 
adverse events. 
Toxicity 
Hold 
Treatment 
for Grade 
Timing for Restarting Treatment 
Treatment Discontinuation / Dosing Continuation  
Neutropenia 
3  
Toxicity resolves to ≤ Grade 2 
Discontinue if toxicity does not resolve within 21 days of last dose 
 
If toxicity resolved within 21 days of the last dose, restart treatment 
at the current dose level.  
 
If grade 3 toxicity reoccurs after resolution, reduced dose by one 
level OR if the current dose level is -1 (5mg) discontinue.  
 
No more than 2 dose reductions are permitted.   
4 
Toxicity resolves to ≤ Grade 2 
Discontinue if toxicity does not resolve within 21 days of last dose 
 
If toxicity resolved within 21 days of the last dose, dose reduce by 
one dose level and restart treatment.  
 
If grade 4 toxicity reoccurs after dose reduction; discontinue 
treatment.  
Thrombocytopenia 
3 
Toxicity resolves to ≤ Grade 2 
Discontinue if toxicity does not resolve within 21 days of last dose 
 
If toxicity resolved within 21 days of the last dose, restart treatment 
at the current dose level.  
 
If grade 3 toxicity reoccurs after resolution and treatment with the 
reduced dose by one level OR if the current dose level is -1 (5mg) 
discontinue.  
 
No more than 2 dose reductions are permitted.   
4 
Toxicity resolves to ≤ Grade 2 
Discontinue if toxicity does not resolve within 21 days of last dose 
 
If toxicity resolved within 21 days of the last dose, dose reduce by 
one dose level and restart treatment.  
 
If grade 4 toxicity reoccurs after dose reduction; discontinue 
treatment 
 
 
The table below is to be used for management of lenalidomide related non-hematologic 
adverse events.  
Toxicity 
Hold 
Treatment 
for Grade 
Timing for Restarting Treatment 
Treatment Discontinuation / Dosing Continuation  
Thromboembolic 
event 
2  
Toxicity resolves to Grade 0 or 1 
Discontinue if toxicity does not resolve within 21 days of last dose 
 
If toxicity resolved within 21 days of the last dose, restart treatment 
at the current dose level.  
 
If grade 2 toxicity reoccurs after resolution and treatment with the 
reduced dose by one level OR if the current dose level is -1 (5mg) 
discontinue.  
 
No more than 2 dose reductions are permitted.   
3 or 4 
Permanently discontinue 
Permanently discontinue 
Treatment related 
secondary 
malignancy 
 
 
Permanently discontinue 
 
Permanently discontinue 


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Toxicity 
Hold 
Treatment 
for Grade 
Timing for Restarting Treatment 
Treatment Discontinuation / Dosing Continuation  
INR or PT 
Increased 
≥2 
Toxicity resolves to baseline 
Discontinue if toxicity does not resolve within 21 days of last dose 
 
If toxicity resolved within 21 days of the last dose, Dose reduce by 
one dose level and restart treatment.  
 
If ≥2 toxicity reoccurs after resolution and treatment with the 
reduced dose by one level OR if the current dose level is -1 (5mg) 
discontinue.  
 
No more than 2 dose reductions are permitted.   
Activated partial 
thromboplastin 
time prolonged 
aPTT 
 
 
≥2 
Toxicity resolves to baseline 
Discontinue if toxicity does not resolve within 21 days of last dose 
 
If toxicity resolved within 21 days of the last dose, Dose reduce by 
one dose level and restart treatment.  
 
If ≥2 toxicity reoccurs after resolution and treatment with the 
reduced dose by one level OR if the current dose level is -1 (5mg) 
discontinue.  
 
No more than 2 dose reductions are permitted.   
Tumor Lysis 
Syndrome 
3 or 4 
Permanently discontinue 
Permanently discontinue 
AST / ALT 
(SGOT/SGPT)   
3 
Toxicity resolves to ≤ Grade 2 
Discontinue if toxicity does not resolve within 21 days of last dose 
 
If toxicity resolved within 21 days of the last dose, restart treatment 
at the current dose level.  
 
If grade 3 toxicity reoccurs after resolution, reduced dose by one 
level OR if the current dose level is -1 (5mg) discontinue.  
 
No more than 2 dose reductions are permitted.   
4 
Toxicity resolves to ≤ Grade 2 
Discontinue if toxicity does not resolve within 21 days of last dose 
 
If toxicity resolved within 21 days of the last dose, dose reduce by 
one dose level and restart treatment.  
 
If grade 4 toxicity reoccurs after dose reduction; discontinue 
treatment.  
All Other Drug-
Related Toxicityc 
3 
Toxicity resolves to ≤ Grade 2 
Discontinue if toxicity does not resolve within 21 days of last dose 
 
If toxicity resolved within 21 days of the last dose, restart treatment 
at the current dose level.  
 
If grade 3 toxicity reoccurs after resolution, reduced dose by one 
level OR if the current dose level is -1 (5mg) discontinue.  
 
No more than 2 dose reductions are permitted.   
4 
Toxicity resolves to ≤ Grade 2 
Discontinue if toxicity does not resolve within 21 days of last dose 
 
If toxicity resolved within 21 days of the last dose, dose reduce by 
one dose level and restart treatment.  
 
If grade 4 toxicity reoccurs after dose reduction; discontinue 
treatment. 
 
 
 
 


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6.3.2 Dose Modifications for Pembrolizumab 
 Dose modifications for Pembrolizumab are not allowed  
 
The table below is to be used for management of pembrolizumab related adverse events. 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or 
3-4 
Hold pembrolizumab for new onset Type 
1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of 
beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
Hyperthyroidism 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while thyroid 
replacement therapy is instituted 
Infusion Reaction 
2b 
Toxicity resolves to Grade 0-1 
Permanently discontinue if toxicity develops despite adequate 
premedication 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related Toxicity 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or inability 
to reduce corticosteroid to 10 mg or less of prednisone or equivalent 
per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline 
and lasts for at least 1 week then patients should be discontinued. 
 
b If symptoms resolve within one hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate   (e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held until symptoms resolve and the subject should be premedicated for the next scheduled dose. 
 
c Patients with intolerable or persistent Grade 2 drug-related AEs,  may hold study medication at physician discretion.  Permanently discontinue study drug for 
persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 
 
 For some grade 3 or 4 toxicities, re-evaluate prior to the next cycle dose; if the 
toxicity resolves to grade 2 or less, resume treatment 


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 For severe autoimmune reactions, initiation of corticosteroids will be 
recommended  
 Permanently discontinue  Pembrolizumab for any severe or Grade 3 drug-related 
AE that recurs or any life-threatening event 
 
6.4 Toxicities and AE management. 
Note: It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of evaluation of a toxicity (or an adverse event)..  
 
 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high 
dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 Diabetes/Hyperglycemia: 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 
3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA). 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  


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 Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in 
thyroid function (at the start of treatment, periodically during treatment, and as indicated 
based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
o Grade 2 hyperthyroidism and Grade 2-4 hypothyroidism events: 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids. 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of completion 


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of infusion.  
Table 1 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
 
Table 1 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
 
 
7.0 Study Agent Information 
7.1 Lenalidomide Information  
7.1.1 Formulation 
This medication comes in an oral capsule preparation. 
 


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7.1.2 Availability 
This medication will be supplied by Celgene. 
 
Because of the embryo-fetal risk, lenalidomide is available only through a restricted 
program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID 
REMS program (formerly known as the RevAssist program) in the United States and for 
study sites outside of the United States through country specific risk minimization 
programs.  
 
Required components of the REVLIMID REMS program include the following:  
 
- Prescribers must be certified with the REVLIMID REMS program by enrolling 
and complying with the REMS requirements.  
 
- Subjects must sign a Patient-Physician agreement form and comply with the 
REMS requirements. In particular, female subjects of reproductive potential who 
are not pregnant must comply with the pregnancy testing and contraception 
requirements and males must comply with contraception requirements.  
 
- Pharmacies must be certified with the REVLIMID REMS program, must only 
dispense to subjects who are authorized to receive lenalidomide and comply with 
REMS requirements. 
 
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site. 
 
Further information about the Revlimid REMS® program is available at 
www.celgeneriskmanagement.com. 
 
 
7.1.3 Solution preparation 
N/A 
 
7.1.4 Storage requirements 
Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F). 
 
7.1.5 Stability 
This agent is stable at room temperature. 
 
7.1.6 Route of administration 
Oral 
 
7.2 Pembrolizumab Information 
7.2.1 Formulation 


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This medication is supplied in a carton containing 100 mg lyophilized powder in one 
single-use vial. 
 
7.2.2 Availability 
This medication will be supplied by Merck. 
 
7.2.3 Solution preparation 
To be reconstituted and diluted prior to IV infusion. 
 
7.2.4 Storage requirements 
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F). 
 
7.2.5 Stability 
Stable when refrigerated. 
 
7.2.6 Route of administration 
Intravenous 
 
7.3 Drug Ordering, Storage and Handling 
Following submission and approval of the required regulatory documents, participation in the 
study initiation meeting and receipt of the site activation letter from the OCR Regulatory 
Coordinator, the initial order may be placed.   
 
Drug order forms and ordering procedure will be presented at the site initiation meeting. 
 
7.4 Destruction of Drug   
At the time of study closure, the unused, used and expired study drug will be destroyed at the 
site per Institutional SOPs unless otherwise specified. 
 
7.5 Records to be kept at Site; Dispensing and Accountability 
It is the responsibility of the Investigator to ensure that a current record of investigational 
product disposition is maintained at each study site where investigational product is 
inventoried and disposed.  Records or logs (supplied by OCR) must comply with applicable 
regulations and guidelines, and should include: 
 Amount received and placed in storage area. 
 Amount currently in storage area. 
 
 Label ID number or batch number. 
 Dates and initials of person responsible for each investigational product inventory 
entry/movement. 
 Amount dispensed to and returned by each patient, including unique patient identifiers. 
 Amount transferred to another area for dispensing or storage. 
 Non-study disposition (e.g., lost, wasted, broken). 
 


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8.0 Correlative / Special Studies 
We will assess PD-LI status (when possible) via immunohistochemistry on initial tumor samples 
collected from an archival tissue sample and fresh biopsy taken prior to cycle 1 day 1. We will 
also analyze pretreatment serum samples for soluble PD-L1. We will then correlate the PD-L1 
status of tumors for treatment efficacy.  
 
We will assess baseline immunophenotypic profiles from the peripheral blood with follow-up 
sampling at established time points throughout the study, including the following: 
 
1)  General proportions of blood immune cells and activation markers by flow cytometry: CD45, 
CD3, CD4, CD8 (T cells), CD19 (B cells), CD14, CD16 (monocytes), CD56 (NK cells), CD11c, 
HLA-DR, CD303, CD66b (myeloid – DCs and granulocytes). Differentiation status of CD4 and 
CD8 T cells (naïve/effector memory/central memory/regulatory/ TCR) as defined by: CD62L, 
CD45RA, CD127, CD25.  Activation markers will include CD69, CD25, HLA-DR, IL-15Ra, 
perforin, Ki67, NKp44, CD57. Immune checkpoint receptors: PD-1, CLTA-4, LAG-3, TIM-3.  
Due to pembrolizumab blockade of PD-1 in treated patients, both pretreatment and post-
treatment samples will be saturated with pembrolizumab, washed, and stained with fluorophore-
conjugated anti-human IgG4, which we have found to efficiently stain PD-1 on leukocytes. For 
these studies we will collect samples prior to treatment on Day 1 of Cycle 1, prior to treatment 
on Day 1 of Cycle 2, and at the time of progression 
 
2) NK cell degranulation assay by flow cytometry: CD107A expression after 2 hour co-culture 
with the EBV-transformed B cell line, 721.221, without and with rituximab (ADCC conditions).   
 
3) Assays to measure cytokines and chemokines (Luminex; available at FCCC) associated with 
Th1/Tc1 responses (e.g. IFN-g, TNF, IL-2), Th2/Tc1 responses (e.g. IL-4, IL-5, IL-10), pro-
inflammatory innate responses (e.g. IFN-α, IL-1β, IL-6, IL-17), homeostatic lymphocyte 
expansion (e.g. IL-7, IL-15) and chemotaxis of immune cells (e.g. IP-10, MCP-1, MIP-1α, MIP-
1β, RANTES). For these studies samples will be collected prior to treatment on Day 1 of Cycle 1 
and post treatment at 2, 4, 24 hours.  Samples will also be collected prior to treatment on Day 1 
of Cycle 2, and at time of progression. 
 
4) Using Nanostring® technology (available at FCCC) we intend to interrogate the immune 
composition of tumors using their PanCancer Immune Profiling Panel as an exploratory 
endpoint. 
 
5) Evaluation of stromal activation status in the tumor microenvironment (Cukierman’s lab) by 
using simultaneous multi-channel immunofluorescent analysis (SMIA) immunohistological 
approach on available tumor biopsies and gather qualitative and quantitative data indicative of 
levels of desmoplastic occurrences and fibroblastic activation (i.e., myofibroblastic) via newly 
written batch analysis software, “SMIA-CUKIE,” which is publicly available online at 
https://github.com/cukie/SMIA-CUKIE .  
 
6) We will store the remaining blood and tissue samples for future studies.


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9.0 Study Calendar 
  
Pre-Study B 
Cycle 1 
Cycle 2 
Cycles 3 + 4 
Cycle 5 + 
Off Study 
Follow up F 
  
  
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
Day 
1 
Day 
8 
Day 
15 
  
  
Informed consent & 
HIPAA A 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical history 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Weight 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
β-HCG 
X D 
X D 
X D 
X D 
X D 
  
  
X D  
  
  
X D  
  
  
X D  
X D  
Physical exam 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
Concurrent meds 
X 
  
  
EKG (as indicated) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital signs (T, P, R, BP) 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
Performance status 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
Serum chemistry C 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
X 
  
TSHᴷ 
X 
Xᴷ 
 
 
 
 
 
Xᴷ 
 
 
 
 
 
 
 
PT, aPTT and INR 
X 
X 
  
  
X 
  
  
X 
  
  
X 
  
  
X 
  
Correlative Blood 
Samples  
 
X H 
  
  
X H 
  
  
  
  
  
  
  
  
X H 
  
Tumor Tissue 
Collection 
X I 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Lenalidomide 
Pregnancy Prevention 
Counseling 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Adverse event 
evaluation 
  
X 
X G 
Tumor Imagingʲ 
X 
Imaging is repeated every 6 weeks regardless of dose delays.  Documentation (radiologic) 
must be provided for patients removed from study for progressive disease. 
X E 
  
A: Informed consent must be signed within 30 days of registration.  If signature is outside that window the patient must sign a new consent. 
B: Pre-study H&P and all labs must be < 30 days prior to Day 1 of Cycle 1.  Tumor measurements and radiologic evaluations must be < 30 days prior to Day 1 of 
Cycle 1.   
C: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT 
[AST], SGPT [ALT], sodium. 
D: Serum pregnancy test (women of childbearing potential) must be completed 10-14 days prior to registration, within 24 hours prior to the first dose of 
Lenalidomide, and then weekly through Cycle 2, Day 1.  To be repeated on Day 1 of every Cycle thereafter, at time of discontinuation, and 28 days after the 
final dose of Lenalidomide is administered. 
E: Off-study evaluation.  If PD documented during scheduled on-study assessment, tumor measurements and radiologic staging do not need to be repeated.   
F: Follow up for PD, resolution of treatment related toxicities, survival should be conducted every 3 months for 1 year or until death, whichever occurs first. 
G: AE and ECI follow-up shall continue until 90 days after the last treatment or until the next treatment begins whichever is less. Pregnancy will be followed for 
up to 120 days after the completion of lenalidomide. 
H: Sample for general proportions of blood immune cells and activation markers by flow cytometry will be collected prior to treatment on Day 1 of Cycle 1, prior 
to treatment on Day 1 of Cycle 2, and at the time of progression. 
 
Sample for assays to measure cytokines and chemokines associated with Th1/Tc1 responses will be collected prior to treatment on Day 1 of Cycle 1 and post 
treatment at 2, 4, 24 hours.  Samples will also be collected prior to treatment on Day 1 of Cycle 2, and at time of progression. 
I: 
Both an archival tumor tissue sample and fresh biopsy will be collected after eligibility is confirmed and prior to the first study treatment on Day 1 of Cycle 1 


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J:     CT scan of the chest and abdomen will be done at baseline and every 6 weeks regardless of dose delays. A brain CT scan with contrast, or brain MRI with 
contrast, must be done at baseline. Brain imaging does not need to be repeated unless clinically indicated. 
K: TSH will be done every 2 cycles starting cycle 1, with free T4 and free T3 done only if TSH is abnormal. If TSH is done at pre-study visit within 30 
days of C1D1, it does not need to be repeated. 


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Version Date 12/9/2016 
10.0 
Adverse Events & Events of Clinical Interest 
10.1 
Definitions 
Adverse Events (AE) is any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, treatment or procedure regardless of whether it is considered 
related to the medical treatment or procedure (NCI CTEP Guidelines March 28, 2011). 
 
Serious Adverse Event (SAE) is an AE that is fatal or life threatening, requires inpatient 
hospitalization or prolongation of existing hospitalization (for > 24 hours), persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, 
or is a congenital anomaly/ birth defect, or results in any important medical event that may 
not result in death, be life threatening, or require hospitalization may be considered an SAE 
when, based upon appropriate medical judgment, may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the above outcomes.  A “life-threatening” 
adverse event places the patient at immediate risk of death in the judgment of the investigator 
or sponsor. 
 
10.1.1 Severity Rating  
The investigator will evaluate the severity of each adverse event.  NCI Common 
Terminology Criteria for Adverse Events (CTCAE v.4.0) or study specific toxicity tables 
provided in the protocol define severity.  If not included in CTCAE v.4.0, severity is 
expressed in numerical grade using the following definitions: 
 
1. Grade 1: Mild-asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated. 
2. Grade 2: Moderate-minimal, local or noninvasive intervention indicated; limiting 
age appropriate instrumental ADL. 
3. Grade 3: Severe-severe or medically significant but not immediately life-
threatening; hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL. 
4. Grade 4: Life-threatening consequences; urgent intervention indicated.  
5. Grade 5: Death related to AE 
 
10.1.2 Attribution/Relationship to study drug  
1. Definite – clearly related 
2. Probable – likely related 
3. Possible – may be related 
4. Unlikely – doubtfully related 
5. Unrelated – clearly not related 
 
10.1.3 Expectedness 
An Expected Adverse Event is one where the specificity or severity is consistent with the 
current information available from the resources. 


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An Unexpected Adverse Event is one where the nature, severity, or frequency of the 
event is related to participation in the research is not consistent with either: 
 
1. The known or foreseeable risk of adverse events associated with the procedures 
involved in the research that are described in (a) the protocol-related documents, 
such as the IRB-approved research protocol, any applicable investigator brochure, 
and the current IRB-approved informed consent document, and (b) other relevant 
sources of information, such as product labeling and package insert, or 
 
2. The expected natural progression of any underlying disease, disorder, or condition 
of the subject (s) experiencing the adverse event and the subjects(s) predisposing 
risk factor profile for the adverse event. 
(OHRP Guidance on reviewing unanticipated problems 2007) 
 
10.1.4 Events of Clinical Interest 
Events of clinical interest (ECI) for this trial include: 
 
1. An overdose of the Merck product. 
 
2. An elevated AST or ALT lab value that is: 
a. Greater than or equal to 3X the upper limit of normal and an elevated total 
bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal  
AND 
 
b. An alkaline phosphatase lab value that is less than 2X the upper limit of 
normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing. 
 
10.2 
Recording and Reporting Responsibilities 
10.2.1 Investigative site recording responsibilities: 
1. Upon identification of an AE,  ECI or SAE, the site investigator will utilize the 
above definitions to properly classify the event.  Each category listed above must 
be recorded for each event. 
 
2. All AEs, ECIs and SAEs will be recorded in the “AE case report forms” (CRF) 
and in progress reports with details about the grade and attribution of each 
episode, action taken with respect to the study drug, and the patient’s outcome 
will be recorded in the CRF.  The study period during which all AEs, ECIs, and 
SAEs must be reported begins at the initiation of study treatment.  All events will 
be recorded on case report forms for the duration of the study until they resolve. 
 
3. All ECI and SAEs will be recorded on the FDA MedWatch form 3500a.  After 
submitting the initial report it may be necessary to submit follow up reports to the 
OCR, Sponsor and the FDA should the event require further investigation. 


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10.2.2 Investigative site reporting responsibilities: 
1. From the time of the first treatment, the investigator/site is responsible to report 
all SAEs and ECIs that occur on or after the first day of study treatment to the 
Investigator-Sponsored Research Unit (ISRU) within 24 hours of becoming aware 
of the event.  SAE and ECI monitoring shall continue until 90 days after the last 
dose of study drug. 
 
2. Each investigator is responsible to report all AEs/SAEs to their local IRB 
following guidelines set by that IRB.  The FCCC OCR reserves the right to 
request an event be reported to the IRB at their discretion.  Copies of events 
reviewed by the IRB must be sent email to the IST Regulatory Specialist at 
SAE.FCCC@fccc.edu.  
 
3. If the investigator or IRB feels the event warrants a revision to the informed 
consent that was not already initiated by the OCR, draft revisions will be made in 
track changes and submitted to the OCR for consideration.  Any consent revisions 
must receive OCR approval prior to submission to the IRB. 
 
4. Any investigator who is in doubt of whether a particular AE needs to be reported 
is directed to call the Study Monitor for confirmation with the Sponsor 
Investigator. 
 
5. If the results of an investigator or OCR investigation show an adverse event not 
initially determined to be reportable is so reportable, the investigator will report 
the event following the above guidelines based on the date the determination is 
made. 
 
6. Copies of all related correspondence and reporting documents must be submitted 
to the OCR Regulatory Coordinator and will be maintained in a regulatory file. 
 
Participating sites should report events to: 
 
Investigator-Sponsored Research Unit 
Office of Clinical Research 
Fox Chase Cancer Center 
215-214-1439 
SAE.FCCC@fccc.edu 
 
10.2.3 OCR Reporting Responsibilities: 
1. Adverse events which meet all of the following criteria must be reported 
to all participating institutions for IRB submission within 2 weeks of 
notification of the event:   
 
i. Unexpected (in terms of nature, severity, or frequency) given (a) the 
research procedures that are described in the protocol-related 


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documents, such as the IRB-approved research protocol and informed 
consent document; and (b) the characteristics of the subject population 
being studied; 
 
ii. Possibly related to participation in the research (possibly related means 
there is a reasonable possibility that the incident, experience, or 
outcome may have been caused by the procedures involved in the 
research); and 
 
iii. Serious (refer to above definition) or otherwise one that suggests that 
the research places subjects or others at a greater risk of physical or 
psychological harm than was previously known or recognized. 
 
2. If the adverse event requires modification of the study protocol and informed 
consent, these changes will be provided to all participating institutions in the 
form of an amendment from the OCR for each site’s IRB of record along with 
the report of the adverse event.   
 
3. Copies of all related correspondence and reporting documents will be 
maintained in a centralized regulatory file for this study at OCR. 
 
4. SAEs that are related, unexpected, fatal, or life-threatening are reportable 
through the Food and Drug Administration (FDA) MedWatch program by 
telephone or fax no later than 7 calendar days after initial receipt of the 
information.  Further information on the timing of submissions are as directed 
by FDA guidelines (http://www.fda.gov/medwatch/index.html).  Serious, 
unexpected events that suggest significant clinical risk will be submitted to 
within 15 calendar days after initial receipt of this information. 
 
Food and Drug Administration: 
Telephone 1-800-332-1088 
Fax 1-800-332-0178 
http://www.fda.gov/medwatch/report.htm 
 
10.2.4 OCR Reporting to Merck 
The ISRU will report ECIs and SAEs to Merck global safety within 2 business days of 
learning of the event, regardless of relationship to pembrolizumab. Reports must be sent 
to: 
 
Merck Global Safety. 
Attn: Worldwide Product Safety 
FAX 215 993-1220 
 
10.2.5 Expedited Reporting by Sponsor-Investigator to Celgene 
For the purpose of regulatory reporting, Celgene Drug Safety will determine the 
expectedness of events of being related to lenalidomide based on the Investigator 


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Brochure.  In the United States, all suspected unexpected serious adverse reactions 
(SUSARs) will be reported in an expedited manner in accordance with 21 CFR 312.32. 
Serious adverse events (SAE) are defined above.  The investigator must inform Celgene 
in writing using a Celgene SAE form or MEDWATCH 3500A form of any SAE within 
24 hours of being aware of the event.  The written report must be completed and supplied 
to Celgene by facsimile within 24 hours.  The initial report must be as complete as 
possible, including an assessment of the causal relationship between the event and the 
investigational product(s).  Information not available at the time of the initial report (e.g., 
an end date for the adverse event or laboratory values received after the report) must be 
documented on a follow-up report.  A final report to document resolution of the SAE is 
required.  The Celgene tracking number (RV-CL-NSCLC-PI-005750) and the 
institutional protocol number should be included on SAE reports (or on the fax cover 
letter) sent to Celgene.  A copy of the fax transmission confirmation of the SAE report to 
Celgene should be attached to the SAE and retained with the patient records 
 
10.2.5.1 Overdose 
 
Overdose, as defined for this protocol, refers to lenalidomide dosing only.   
 
On a per dose basis, an overdose is defined as the following amount over the 
protocol-specified dose of lenalidomide assigned to a given patient, regardless of any 
associated adverse events or sequelae. 
PO 
any amount over the protocol-specified dose 
 
 
IV 
10% over the protocol-specified dose  
 
SC 
10% over the protocol-specified dose 
 
On a schedule or frequency basis, an overdose is defined as anything more frequent 
than the protocol required schedule or frequency.   
 
On an infusion rate basis, an overdose is defined as any rate faster than the protocol-
specified rate.  Complete data about drug administration, including any overdose, 
regardless of whether the overdose was accidental or intentional, should be reported 
in the case report form.    
 
Celgene Drug Safety Contact Information: 
Celgene Corporation 
Global Drug Safety and Risk Management 
Connell Corporate Park 
300 Connell Dr.  Suite 6000 
Berkeley Heights, NJ  07922 
Fax: 
 
(908) 673-9115 
E-mail:  
drugsafety@celgene.com 


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10.3 
Pregnancy  
10.3.1 Pregnancy Reporting for Pembrolizumab 
 
All WOCBP should be instructed to contact the Investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during study 
participation. 
 
In the event of a confirmed pregnancy in a patient participating in the study, the 
Investigator must immediately notify the Fox Chase Cancer Center Study Monitor who 
will notify Dr. Hossein Borghaei.  
 
Pregnancies and lactations that occur from the time of treatment allocation through 120 
days following cessation of pembrolizumab, or 30 days following cessation of treatment 
if the subject initiates new anticancer therapy, whichever is earlier, must be reported by 
the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine 
death, miscarriage and stillbirth must be reported as serious events (Important Medical 
Events). If the pregnancy continues to term, the outcome (health of infant) must also be 
reported. 
 
Such events must be reported within 24 hours to the Sponsor Investigator.  The ISRU will 
report such events within 2 working days to Merck Global Safety. 
 
10.3.2 Pregnancy Reporting for Lenalidomide 
Pregnancies and suspected pregnancies (including a positive pregnancy test regardless of 
age or disease state) of a female subject occurring while the subject is on lenalidomide, or 
within 28 days of last dose of lenalidomide, are considered immediately reportable 
events.  Lenalidomide is to be discontinued immediately. The pregnancy, suspected 
pregnancy, or positive pregnancy test must be reported to Celgene Drug Safety 
immediately by facsimile, or other appropriate method, using the Pregnancy Initial 
Report Form, or approved equivalent form. The female subject may be referred to an 
obstetrician-gynecologist (not necessarily one with reproductive toxicity experience) or 
another appropriate healthcare professional for further evaluation. 
The Investigator will follow the female subject until completion of the pregnancy, and 
must notify Celgene Drug Safety immediately about the outcome of the pregnancy (either 
normal or abnormal outcome) using the Pregnancy Follow-up Report Form, or approved 
equivalent form.  
 
If the outcome of the pregnancy was abnormal (e.g., spontaneous or therapeutic 
abortion), the Investigator should report the abnormal outcome as an AE.  If the abnormal 
outcome meets any of the serious criteria, it must be reported as an SAE to Celgene Drug 


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Safety immediately by facsimile, or otherappropriate method, within 24 hours of the 
Investigator’s knowledge of the event using the SAE Report Form, or approved 
equivalent form. 
 
All neonatal deaths that occur within 28 days of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death after 28 days that the Investigator 
suspects is related to the in utero exposure to the lenalidomide should also be reported to 
Celgene Drug Safety immediately by facsimile, or other appropriate method, within 24 
hours of the Investigator’s knowledge of the event using the SAE Report Form, or 
approved equivalent form. 
 
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, the 
male subject taking lenalidomide should notify the Investigator, and the pregnant female 
partner should be advised to call their healthcare provider immediately 
 
11.0 
Measures of Effect 
Response Evaluation Criteria in Solid Tumors (RECIST)  
The Response Evaluation Criteria in Solid Tumors (RECIST 1.1) criteria will be used for objective 
tumor response assessment.  Assessments will be performed after every six weeks of treatments. 
Once protocol treatment has been completed subjects will be assessed every three months or 
sooner as indicated and judged by treating physicians. 
11.1 
Definitions 
Evaluable for adverse events.  All patients will be evaluable for adverse events from the time 
of their first treatment with pembrolizumab and lenalidomide. 
 
Evaluable for objective response.  Only those patients who have measurable disease present 
at baseline, have received at least two cycles of therapy, and have had their disease re-
evaluated will be considered evaluable for response.  These patients will have their response 
classified according to the definitions stated below.  (Note:  Patients who exhibit objective 
disease progression prior to the end of cycle 1 will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline that 
are evaluable but do not meet the definitions of measurable disease, have received at least 
two cycles of therapy, and have had their disease re-evaluated will be considered evaluable 
for non-target disease.  The response assessment is based on the presence, absence, or 
unequivocal progression of the lesions.  
 
11.2 
Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 
mm with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must 
be recorded in millimeters (or decimal fractions of centimeters). 


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Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis 
will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are 
considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and 
abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline.  Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements.  It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected.  A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline 
sum diameters.  If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum.  The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline.  Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow-
up.  
 
11.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 30 days before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 


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preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions:  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and 10 mm diameter as assessed 
using calipers (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung.  However, CT is preferable.  
 
CT and MRI:  This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).   
 
MRI has excellent contrast, spatial, and temporal resolution; however, there are many image 
acquisition variables involved in MRI, which greatly impact image quality, lesion 
conspicuity, and measurement.  Furthermore, the availability of MRI is variable globally.  As 
with CT, if an MRI is performed, the technical specifications of the scanning sequences used 
should be optimized for the evaluation of the type and site of disease.  Furthermore, as with 
CT, the modality used at follow-up should be the same as was used at baseline and the 
lesions should be measured/assessed on the same pulse sequence.  It is beyond the scope of 
the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all scanners, 
body parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-
CT is not always of optimal diagnostic CT quality for use with RECIST measurements.  
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time.  Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed.   
 
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 
the next.  If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be 
used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation 


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is not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are 
initially above the upper normal limit, they must normalize for a patient to be considered in 
complete clinical response.  Specific guidelines for both CA-125 response (in recurrent 
ovarian cancer) and PSA response (in recurrent prostate cancer) have been published [JNCI 
96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In 
addition, the Gynecologic Cancer Intergroup has developed CA-125 progression criteria 
which are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
Effusions: The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an effusion 
may be a side effect of the treatment) and progressive disease. 
 
11.4 
Response Criteria 
11.4.1 Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  (Note:  the appearance of one or 
more new lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on study. 
 
11.4.2 Evaluation of Non-Target Lesions 
Complete Response (CR): Disappearance of all non-target lesions.  All lymph nodes must 
be non-pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must normalize 
for a patient to be considered in complete clinical response. 


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Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally 
trump target lesion status.  It must be representative of overall disease status change, not 
a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 
11.4.3 Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD 
/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD 
/not evaluated 
No 
SD 
Documented at least once >4 wks. 
from baseline** 
PD 
Any 
Yes or No 
PD 
 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
*** In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as 
disease progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration.”  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 
 
 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 


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CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since 
SD is increasingly used as an endpoint for assessment of efficacy in some trials so 
to assign this category when no lesions can be measured is not advised 
 
11.5 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met for 
CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment until 
the criteria for progression are met, taking as reference the smallest measurements recorded 
since the treatment started, including the baseline measurements.  
 
11.6 
Progression-Free Survival 
Progression-free survival (PFS) will be used in the phase II component of this study.  PFS is 
defined as the duration of time from start of treatment to time of disease progression or death, 
whichever occurs first. 
 
12.0 
Statistical Considerations 
12.1 
Study Design/Endpoints 
The primary endpoint for the phase I component of this protocol will be determining the 
maximum tolerated dose (MTD) of lenalidomide in combination with pembrolizumab. Our 
hypothesis is that the drugs pembrolizumab and lenalidomide will be well-tolerated in 
combination, without significant toxicities or adverse events.  
 
The primary endpoint for the phase II component of this protocol will be determining 
efficacy as measured by progression free survival (PFS), and our hypothesis is that this novel 
drug combination will improve PFS as described below. We will test the null hypothesis that 
at most 25% of patients will be progression free for 20 weeks. Our alternative will be that at 
least 50% of them will with our combination therapy. Using the assumption of exponential 
PFS we would expect 50% or 71% to survive for 10 weeks under the null or alternative 
respectively. We will initially enter 13 patients to a two-stage design with early stopping in 
both time and patient number. If at least 7 of these 13 patients are PF for 10 weeks then we 
will enter 13 new patients to the study. In this case PF patients from the initial cohort will 
stay on study and, finally, if at least 11 of 26 patients are PF for 20 weeks we will reject the 
null hypothesis. If 6 or fewer patients are PF at 10 weeks we will not recruit additional 


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patients, terminate the study for lack of efficacy and accept the null hypothesis. The study 
has 81% overall power and 3.5% type I error. The chance of early stopping in both time and 
patient number is 50% under the null and 5.5% in error. 
 
12.2 
Toxicity 
In the phase I part of the study, a ‘3+3” standard design, the chance of dose escalation, given 
the true toxicity is shown in the following table. For example, if the true toxicity is 50% the 
chance of dose escalation is 17.2%. 
 
ptox                0.1       0.2       0.3       0.4       0.5       0.6       0.7 
p(escalate)     0.906   0.709   0.494   0.309   0.172   0.082   0.032 
 
We consider 18% rate of DLTs acceptable and 40% excessive. If 6 of the initial 13 phase II 
patients experience DLTs, the trial will be halted and dose reduction considered. Finally, if 
ever 9 patients of the 26 patients experience DLTs, the treatment will be considered too 
toxic. The chance of early halting when the true toxicity is 40% is 44% and is 1.8% when the 
true toxicity is only 18%. The toxicity design has 80% power to declare the treatment too 
toxic when it is, and 4.2% chance of this declaration in error. 
 
12.3 
Sample Size/Accrual Rate 
The planned sample size for the phase I component will be 6-18 patients; we will plan to 
accrue 1-2 patients per month. 
 
The planned sample size for the phase II component is 26 patients; we will plan to accrue 2-4 
patients per month 
 
12.4 
Stratification Factors 
Patients in the phase I component of the study will not be stratified. 
 
Patients in the phase II component of the study will be stratified by subtype of lung cancer 
(e.g. adenocarcinoma, squamous cell carcinoma) and number of prior lines of therapy.  
 
12.5 
Analysis of Secondary Endpoints 
95% confidence bounds will be computed for the tumor response rate. Frequencies of T and 
NK cell subsets will be tabulated with 95% confidence bounds. Activation phenotypes will 
be tabulated with corresponding 95% confidence bounds.  The association of PD-L1 
expression level (above or below the grand median) with tumor response will be submitted to 
Fisher’s exact test.    
 
 
 
 
12.6 
Reporting and Exclusions 
12.6.1 Evaluation of toxicity 


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All patients will be evaluable for toxicity from the time of their first treatment with 
pembrolizumab and lenalidomide.  
 
12.6.2 Evaluation of response 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early 
death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
 
All of the patients who met the eligibility criteria (with the possible exception of those 
who received no study medication) should be included in the main analysis of the 
response rate.  Patients in response categories 4-9 should be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or drug 
administration does not result in exclusion from the analysis of the response rate.  Precise 
definitions for categories 4-9 will be protocol specific.  
 
13.0 
Data and Safety Monitoring Plan 
13.1 
Monitoring Plan  
FCCC OCR will monitor the medical and study records of each participant accrued 
throughout the course of the study.  In addition, the OCR will collect and report data to the 
Sponsor Investigator who will review these data on a regular basis at a rate dependent on 
subject accrual.  All serious adverse events (SAEs) will be reviewed on a real time basis first 
by the study site PI and subsequently by the OCR and Sponsor Investigator as applicable. 
 
13.2 
Data Safety Monitoring Committee   
Interim analysis of toxicity, outcome and ongoing scientific investigations may be performed 
at least every 6 months by the Fox Chase Cancer Center Data Safety Monitoring Committee 
(FCCC DSMC).  In this capacity the FCCC DSMC will serve as an advisory committee to 
the OCR.  The FCCC DSMC will review those aspects of this trial that are outlined in the 
responsibilities section of the Data and Safety Monitoring Plan (DSMP).  If the committee 
decides that changes should be made to this trial, it will make recommendations in writing to 
the Sponsor Investigator, the Associate Director of Clinical Research, and the Protocol 
Management Executive Committee, which, in turn, have the authority to approve or 
disapprove these recommendations.  These changes will be discussed with the Sponsor 
Investigator before they are implemented.  These changes may include early termination of 
accrual.  Other changes might include altering the accrual goals or changing the eligibility 
criteria for the trial. 
 
 
14.0 
Administrative   


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This study will be conducted in accordance will local, state and Federal regulations and 
according to accepted good clinical practice guidelines. 
 
14.1 
Data Reporting 
The FCCC Study Monitor will request case report forms to be completed within 2 weeks of 
the protocol visit.  Participating sites are responsible to respond to queries prior to the next 
scheduled monitoring visit.   
 
The ERP Data Manager is responsible for compiling and submitting data to the sponsor 
investigator and statistician on an ongoing basis for monitoring as described in the data safety 
monitoring plan and reporting to the Data and Safety Monitoring Committee. 
 
All patient information will be stored in an EDC system accessible only to the study team 
members for the purpose of entering, reviewing and analyzing data.  Any paper records, such 
as case report files, produced will be stored in a secure location.  
 
The IST Regulatory Specialist is responsible for distributing and tracking review of all IND 
Action Letters, Safety Reports, study specific Serious Adverse Events. 
 
14.2 
Retention of Records   
Time points for the retention of records are described in detail in the contract between the 
grantor and the OCR and passed on to the participating site.  Please refer to the study specific 
terms for specific time points.  In all cases the Study Monitor must be notified of any plans to 
move records to an offsite location prior to doing so. 
 
14.3 
Study Agents 
Any study agent supplied through the OCR from the manufacturer or a third party distributor 
may not be used for any purpose outside the scope of this protocol.  The agent may not be 
transferred to any party not participating in the clinical trial. 
 
14.4 
Informed Consent 
The IRB approved informed consent documents must be signed by the patient, or the 
patient’s legally authorized representative, before his or her participation in the study.  The 
case history for each patient shall document that informed consent was obtained prior to 
participation in the study.  A copy of the informed consent documents must be provided to 
the patient or the patient’s legally authorized representative.  If applicable, they will be 
provided in a certified translation of the local language. 
 
Original signed consent forms must be filed in each patient’s study file or medical record 
with a copy in the study file. 
 
 
 


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15.0 
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16.0 Appendix A: Lenalidomide Pregnancy Prevention Plan 
 


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