Clinical trial NCT04381988
Conditions: COVID-19 Cancer
Keywords: Hydroxychloroquine Radiotherapy 20-176
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2020-05-07; Completion date: 2021-04-21
Enrollment: 4 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The researchers are doing this study to find out whether the study drug hydroxychloroquine can prevent infection with the COVID-19 virus, compared with placebo, in people who are receiving radiation therapy for their cancer. The placebo used in this study is a tablet that looks the same as the study drug and is taken in the same way, but it does not contain any active ingredients.

Detailed description:

Arms: arm 1: Every patient on trial must be scheduled to receive at least 10 radiation treatments prior to initiation of hydroxychloroquine 400mg daily. arm 2: Every patient on trial must be scheduled to receive at least 10 radiation treatments prior to initiation of placebo 400mg daily.
Interventions: intervention 1: Hydroxychloroquine intervention 2: Placebo intervention 3: Radiation therapy
Intervention descriptions: intervention 1: 400mg daily intervention 2: 400mg daily intervention 3: Standard radiation therapy will be prescribed and administered as per the patient's radiation oncologist.

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 1 of 60 
 
 
 
 
 
A PHASE II RANDOMIZED DOUBLE-BLIND PLACEBO-CONTROLLED CLINICAL TRIAL OF 
HYDROXYCHLOROQUINE FOR PROPHYLAXIS AGAINST COVID-19 IN PATIENTS 
RECEIVING RADIOTHERAPY 
 
 
 
MSK PROTOCOL 
 
 
 
Principal 
Investigator/Department: 
Nancy Y. Lee, MD 
Radiation Oncology 
Co-Principal 
Investigator(s)/Department: 
Yao Yu, MD 
Linda Chen, MD 
Eric Sherman, MD 
Radiation Oncology 
Radiation Oncology 
Medicine 
Investigator(s)/Department: 
Chris Barker, MD 
Simon N. Powell, MD, PhD 
Nadeem Riaz, MD 
Narek Shaverdian, MD 
Paul Romesser, MD 
Daphna Gelblum, MD 
Kaveh Zakeri, MD 
Zhigang Zhang, PhD 
Ngolela Esther Babady, PhD 
Lakshmi Ramanathan, PhD 
Ellinor Peerschke, PhD 
Melissa Pessin MD, PhD 
Carol Chen, MD 
Michelle Ginsberg, MD 
Rocio Perez Johnston, MD 
Genovefa Papanicolaou, MD 
Mimi Kamboj, MD 
Susan Seo, MD 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Epidemiology-Biostatistics 
Laboratory Medicine 
Laboratory Medicine 
Laboratory Medicine 
Laboratory Medicine 
Medicine 
Radiology 
Radiology 
Medicine 
Medicine 
Medicine 
Consenting 
Professional(s)/Department: 
Marisa Kollmeier, MD 
Andreas Rimner, MD 
Carla Hajj, MD 
Lior Braunstein, MD 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 2 of 60 
 
 
 
 
 
Jillian Tsai, MD, PhD 
Marsha Reyngold, MD 
Richard Gewanter, MD 
Boris Mueller, MD 
Borys Mychalczak, MD 
Melissa Remis Zinovoy, MD 
Annemarie F. Shepherd, MD 
John Cuaron, MD 
Sean McBride, MD, MPH 
Christopher Crane, MD 
Daniel Gomez, MD 
Daniel Shasha, MD 
Michael J. Zelefsky, MD 
Beryl McCormick, MD 
Oren Cahlon, MD 
Kaled M. Alektiar, MD 
Samuel F. Bakhoum, MD 
Kathryn Beal, MD 
Erin Gillespie, MD 
Daniel Gorovets, MD 
Daniel S. Higginson, MD 
Adam Schmitt, MD 
Charles B. Simone, MD 
Suzanne L. Wolden, MD 
Abraham J. Wu, MD 
Amy Xu, MD, PhD 
Yoachim Yahalom, MD 
Yoshiya Yamada, MD 
T. Jonathan Yang, MD 
Divya Yerramilli, MD 
Michael Bernstein, MD 
Fumiko Chino, MD 
Philip Gilbo, MD 
Craig E. Grossman, MD, PhD 
David M. Guttman MD 
Jung Julie Kang, MD, PhD 
Atif Jalees Khan, MD 
Quincey LaPlant, MD 
Justin Mann, MD 
Dhwani R. Parikh, MD 
Jacob Y. Shin, MD 
Richard Tuli, MD, PhD 
Laura Dover, MD 
Chris Barker, MD 
Simon N. Powell, MD, PhD 
Nadeem Riaz, MD 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 3 of 60 
 
 
 
 
 
Narek Shaverdian, MD 
Paul Romesser, MD 
Daphna Gelblum, MD 
Kaveh Zakeri, MD 
Nancy Y. Lee, MD 
Linda Chen, MD 
Yao Yu, MD 
Eric Sherman, MD 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Radiation Oncology 
Medicine 
 
 
Please note: All listed above must have completed the mandatory Human Subjects 
Education and Certification and Good Clinical Practice Certification Programs. 
 
 
OneMSK Sites 
Site Name 
Site’s Role 
Manhattan 
All Protocol Activities 
Basking Ridge 
All Protocol Activities 
Bergen 
All Protocol Activities 
Commack 
All Protocol Activities 
Monmouth 
All Protocol Activities 
Westchester 
All Protocol Activities 
Nassau 
All Protocol Activities 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 4 of 60 
 
 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
8 
Figure 1.2: Protocol Timeline 
9 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
9 
2.2 Primary Objectives: 
9 
2.3 Secondary Objectives: 
10 
2.4 Correlative studies (if specimen is available): 
10 
3.1 
BACKGROUND AND RATIONALE 
10 
3.2 SARS-CoV-2 and Cancer 
10 
3.3 Preclinical Efficacy of Chloroquine and Hydroxychloroquine in Coronaviruses 
11 
3.4 Rationale for Clinical Investigation 
11 
3.5 Rationale for hydroxychloroquine dosing of 400mg daily 
12 
3.6 Rationale for Duration of Hydroxychloroquine Prophylaxis 
13 
3.7 Hydroxychloroquine in combination with radiation and chemotherapy in cancer 
13 
3.8 Risk of Infection Over Time 
15 
3.9 Estimate of effect size for hydroxychloroquine 
19 
3.10 
R
ationale for use of SARS-Cov-2 PCR, Rapid Standard COVID-19 Antigen and Serology tests
 19 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
22 
4.2 Design 
22 
4.3 Intervention 
23 
4.3.1. Baseline Assessment 
23 
4.3.2. SARS-CoV-2 PCR Testing and rapid Standard COVID19 Antigen test 
23 
4.3.3. SARS-CoV-2 Serologic Testing 
24 
4.2.5. Randomization Timing Instructions 
25 
4.2.6. Drug administration 
25 
4.2.7. Radiation therapy: 
26 
4.2.8. Chemotherapy: 
26 
4.2.9. Symptom screening and toxicity assessments: 
27 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 5 of 60 
 
 
4.2.10. On-treatment or post-treatment SARS-CoV-2 testing: 
27 
4.2.11. SARS-CoV-2 positive patients: 
27 
4.3 Estimated Duration of Subject Participation 
28 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC ASSESSMENTS 
28 
5.2 Hydroxychloroquine 
28 
5.2.1. Description: 
28 
5.2.2. Pharmacokinetics: 
28 
5.2.3. Supply: 
29 
5.2.4. Hydroxychloroquine formulation, packaging, and storage 
29 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
30 
6.2 Participant Inclusion Criteria: 
30 
6.3 Participant Exclusion Criteria: 
31 
7.0 
RECRUITMENT PLAN 
31 
7.1. Research Participant Registration 
32 
7.2 CRDB Blinded Randomization 
32 
7.3 Breaking the Blind 
33 
8.0 INFORMED CONSENT PROCEDURES 
33 
9.1 
PRETREATMENT EVALUATION/INTERVENTION 
34 
9.2 Management of patients based on Rapid serology and Antigen testing 
34 
10.1 
TREATMENT/INTERVENTION PLAN 
35 
10.2 Dosing Instructions and Schedule 
35 
10.2.1. Hydroxychloroquine Dosing Instructions and Schedule 
35 
10.1.2 Radiation Dosing Instructions and Schedule 
35 
10.1.3 Chemotherapy Dosing Instructions and Schedule 
36 
10.2 Concomitant Medications and Therapies 
36 
10.2.1 Permitted concomitant therapy includes: 
36 
10.2.2. Excluded Concomitant Medications 
36 
10.3 Hydroxychloroquine Dose Modification and Discontinuation 
37 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 6 of 60 
 
 
10.3.1 Initial Hydroxychloroquine Dose 
37 
10.3.2. Hydroxychloroquine Dose Modifications and Discontinuation During Treatment 
37 
11.1 EVALUATION DURING TREATMENT/INTERVENTION 
39 
11.2 Study Calendar 
39 
12.0 CRITERIA FOR REMOVAL FOR STUDY 
40 
13.1 CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY 
41 
13.2 Criteria for Therapeutic Response/Outcome Assessment 
41 
13.3 Criteria for Study Endpoint Evaluability 
42 
14.0 BIOSTATISTICS 
42 
15.1 TOXICITIES/SIDE EFFECTS 
44 
15.2 Serious Adverse Event (SAE) Reporting 
44 
15.3 External SAE Reporting 
45 
15.4 Attribution of the AE: 
45 
15.5 Drug Interactions with Hydroxychloroquine 
46 
15.6 Hydroxychloroquine - Potential Adverse Events 
46 
15.7 Principles of Adverse Event Management 
48 
16.1 PROTECTION OF HUMAN PARTICIPANTS 
49 
16.2 Privacy 
50 
16.3 Data Management 
50 
16.4 Quality Assurance 
50 
16.5 Data and Safety Monitoring 
50 
17.0  REFERENCES 
52 
18.1 APPENDICES 
56 
18.2 COVID19 Symptoms 
56 
18.2.  MSKCC Radiation Oncology Department Guidelines for Radiation Therapy in COVID19- 
positive or COVID19 suspected patients (as of 3/24/2). 
57 
18.3 QT Prolonging agents 
59 
18.4 Management Algorithm for Positive Screen 
59 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 7 of 60 
 
 
 
 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA 
 
Patients receiving radiotherapy are at high risk for infection with Severe Acute Respiratory 
Syndrome Coronavirus 2 (SARS-CoV-2), due to frequent and close contact with healthcare 
workers and other patients, older age, and compromised immune systems. Following infection, 
these patients are at high risk for severe infectious complications that can require hospitalization 
critical care, and can potentially lead to death.  This is a phase II placebo-controlled, double- 
blinded, randomized study evaluating hydroxychloroquine  as prophylaxis  against coronavirus 
disease 19 (COVID-19) among patients with no history of SARS-CoV-2 infection who are 
receiving radiotherapy for cancer. 
 
The primary eligibility criteria is based on a symptom screen and risk factors for prior COVID-19 
exposure or infection. Clinical criteria include: no history of SARS-CoV-2 infection; no COVID- 
19-like symptoms (Temp >38.0C in addition to sore throat, cough, shortness of breath, 
wheezing, chest tightness, body aches/myalgias, chills, diarrhea, or anosmia) within 14 days of 
enrollment; and no close contacts with confirmed SARS-CoV-2 patients within 14 days. The 
patient must meet clinical criteria to enroll. The clinical criteria is based on the standard MSKCC 
COVID-19 screening guideline plus several additional criteria, such as no history of anosmia 
and diarrhea. Patients with symptoms and negative COVID-19 PCR or negative COVID-19 
serology will be allowed to enroll. 
 
At the time of protocol writing, COVID-19 testing capabilities at MSKCC include SARS-CoV-2 
PCR. A serologic assay for anti-SARS-CoV-2 IgG and IgM is being validated and will become 
available prior to protocol opening.  \We also allow optional laboratory-based criteria to be 
accounted for in our enrollment criteria. We have obtained a set of Standard Q COVID-19 
IgM/IgG  rapid immunochromatographic tests manufactured by SD Biosensor and distributed to 
us for the trial by Henry Schein Inc.  Additional optional criteria also includes the rapid Standard 
COVID-19 Ag test manufactured by SD Biosensor and distributed to us for the trial by Henry 
Schein Inc. Any of the above tests, when available, must be negative prior to enrollment. Thus, 
the rapid antigen and serology tests are optional, and will only be done if personal protective 
equipment (PPE) is available and if testing does not interfere with available resources at 
MSKCC. 
 
Patients who meet all eligibility criteria will be randomized 1:1 to receive hydroxychloroquine 
400mg daily versus placebo at the start of radiation therapy. Every patient on trial must be 
scheduled to receive at least 10 radiation treatments prior to initiation of hydroxychloroquine or 
placebo. Patients will receive hydroxychloroquine  concurrently with at least 10 radiation 
treatments and will then continue hydroxychloroquine or placebo for 14 days after completion of 
radiotherapy. Our primary objective is to compare the cumulative incidence of SARS-CoV-2 
infection within 9 weeks of randomization for patients receiving radiotherapy with prophylactic 
hydroxychloroquine versus placebo.  We will randomize n=132 patients. If the protocol accrues 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 8 of 60 
 
 
 
 
100 patients within the first 28 days of activation, it will be amended to expand to n=166, as 
described in the biostatistics section. Proton therapy is permitted for this protocol at ProCure 
and NYPC. 
 
 
Figure 1.1 Schema 
 
 
 
Figure 1.2: Protocol Timeline 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 9 of 60 
 
 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
2.2 Primary Objectives: 
● To compare the cumulative incidence of  SARS-CoV-2 infection (Section 13.1) within 9 
weeks from randomization in patients receiving radiotherapy with prophylactic 
hydroxychloroquine versus placebo. 
 
2.3 Secondary Objectives: 
● To compare the cumulative incidence of severe COVID-19 or death (Section 13.1) within 
12 weeks of randomization in patients receiving radiotherapy with prophylactic 
hydroxychloroquine versus placebo. 
● To compare the cumulative incidence of symptomatic COVID-19 (Section 13.1) within 9 
weeks of randomization in patients receiving radiotherapy with prophylactic 
hydroxychloroquine vs placebo. 
● To compare the cumulative incidence of acute grade ≥3 toxicity in patients receiving 
radiotherapy with prophylactic hydroxychloroquine  versus placebo within 12 weeks of 
randomization. 
 
2.4 Correlative studies (if specimen is available): 
● To evaluate the baseline prevalence of anti-SARS-CoV-2 antibodies in patients receiving 
radiation and chemoradiation without history of symptomatic COVID-19 
● To correlate the qualitative Standard Q COVID-19 IgM/IgG  rapid 
immunochromatographic test manufactured by SD Biosensor with quantitative SARS- 
CoV-2 serology tests (assays being validated in MSKCC Laboratory Medicine) in 
patients where banked serology is available. 
● To correlate the rapid Standard COVID-19 Ag test manufactured by SD Biosensor and 
distributed to us for the trial by Henry Schein Inc. with the SARS-Co-V-2 RT PCR, only in 
patients where RT-PCR data is available. 
● In patients who are serology negative, to compare the cumulative incidence of 
symptomatic COVID-19 within 9 weeks from randomization to prophylactic 
hydroxychloroquine versus placebo 
● In patients who are serology negative, to compare the cumulative incidence of severe 
COVID-19 within 12 weeks from randomization to prophylactic hydroxychloroquine 
versus placebo 
● Collected serum will be stored for future studies 
 
3.1 
BACKGROUND AND RATIONALE 
 
3.2 SARS-CoV-2 and Cancer 
SARS-CoV-2 is a highly contagious novel coronavirus that is the cause of COVID-19, a disease 
associated with high rates of viral pneumonia, morbidity, and mortality, particularly in 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 10 of 60 
 
 
 
 
susceptible populations. As of 3/26/2020, the World Health Organization reports 489,718 
confirmed cases and 22,171 deaths.  In the United States, 40-50% of the population is 
conservatively projected to become infected. SARS-CoV-2 disproportionately impacts patients 
who are elderly, immunocompromised, male, and those with comorbidities.2–4 
 
The cancer patient population is at high risk of infection due to frequent exposures to the 
healthcare workers, other patients, and immunosuppression from their cancer. Once infected, 
cancer patients face high rates of severe infections requiring hospitalization, critical care, 
ventilator support, and ultimately high rates of death. The mortality rate in cancer patients is the 
highest among any reported subset. Liang et al. report a 34% risk of intensive care unit 
requirements, ventilation use, and death among SARS-CoV-2 patients with cancer compared to 
8% of SARS-CoV-2 patients without cancer.4  Moreover, among cancer patients – those who 
undergo surgery or receive cytotoxic chemotherapy within one month of infection were at the 
highest risk.  In Italy, cancer patients comprised 4.6% of the population5  but represented 20% of 
all COVID-19 related deaths.6 
 
3.3 Preclinical Efficacy of Chloroquine and Hydroxychloroquine in Coronaviruses 
Chloroquine and hydroxychloroquine are quinine compounds that are well tolerated and widely 
used for decades for both malaria prophylaxis and treatment as well as in the management of 
chronic rheumatological diseases, such as rheumatoid arthritis and systemic lupus 
erythematosus. Importantly, chloroquine has broad-spectrum antiviral properties and is a potent 
inhibitor of coronaviruses including SARS-CoV-1, inhibiting viral fusion and replication in-vitro.7–9 
Mechanistically, chloroquine interferes with sialic acid biosynthesis  – which coronaviruses  
utilize as moieties for ligand recognition.  In SARS-CoV-1, chloroquine also impacts the 
glycosylation of a viral cell surface receptor, angiotensin-converting enzyme 2 (ACE2).10 
Additionally,  chloroquine has been demonstrated to interfere with viral-endosomal membrane 
fusion in SARS-CoV-1, increasing endosomal pH, and abrogates the release of the viral 
genome. Hydroxychloroquine  is a derivative of chloroquine that is associated with dec reased 
toxicity and has demonstrated antiviral activity against SARS-CoV-2 in vitro.11   Based on in vitro 
data, hydroxychloroquine is also thought to inhibit viral replication by preventing glycosylation of 
the ACE2 receptor, glycosylation of the viral spike protein used for infecting the host cell, and by 
reducing the acidification of intracellular organelles, which is essential for viral membrane 
fusion.11    Thus, chloroquine and hydroxychloroquine have the potential to therapeutically inhibit 
viral fusion and replication in SARS-CoV-2. 
 
3.4 Rationale for Clinical Investigation 
Hydroxychloroquine  is an inexpensive and well-tolerated drug with a well-established safety 
profile.  It has known anti-viral activity and is highly efficacious for malaria chemoprophylaxis. 
With regard to SARS-CoV-2 clinical data, Chinese investigators published a narrative 
description of 100 SAR-CoV-2 patients treated on a clinical trial with chloroquine and report: 
rapid decline in fever, improved clinical findings on thoracic imaging, and decreased recovery 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 11 of 60 
 
 
 
 
time.7, 12, 13 As a result of favorable toxicity profile and potential efficacy, many on-going trials are 
testing hydroxychloroquine  as a treatment for COVID-19. Emerging data demonstrate that 
hydroxychloroquine is well tolerated in patients with COVID-19 and may be associated with 
reduced viral load; however, the ability of hydroxychloroquine to prevent infection in a high-risk 
population remains unknown.14    Therapeutic and/or prophylactic use has been recommended 
internationally by an expert consensus group of the Department of Science and Technology of 
Guangdong Province in China, the Dutch Center of Disease Control, and the Italian Society of 
Infectious and Tropical disease. Notably, hydroxychloroquine  is undergoing expedited review for 
use in SARS-CoV-2 by the United States Food and Drug Administration.12,  13, 15  To date, only 
one randomized clinical trial of hydroxychloroquine  has demonstrated a benefit. 62 patients 
hospitalized for mild COVID-19 viral pneumonia were randomized 1:1 to hydroxychloroquine 
200mg twice daily for 5 days. The authors reported that hydroxychloroquine was associated  
with shorter time to remission of fever and cough and greater improvements in radiographic CT 
findings based on serial scans. Importantly, all four patients that decompensated and developed 
“severe” viral pneumonia were in the control group.16 
 
In light of the current public health emergency, and widespread infection risk, we are in urgent 
need of effective risk reduction strategies for our cancer patients as we await effective 
therapeutic options. Patients receiving daily radiation treatments for cancer in SARS-CoV-2 
endemic areas are at increased exposure risk. These patients are also at high risk for infection 
due to treatment-related immunosuppression.  Therefore, in the setting of the current pandemic, 
we propose a clinical trial investigating the use of daily prophylactic hydroxychloroquine in 
cancer patients undergoing radiation therapy.   We hypothesize that prophylactic 
hydroxychloroquine will reduce the risk of symptomatic SARS-CoV-2 infection, hospitalizations, 
and disease morbidity in the high-risk cancer population receiving radiation therapy. 
 
3.5 Rationale for hydroxychloroquine dosing of 400mg daily 
Liu et al. recently studied the in vitro efficacy of both chloroquine and hydroxychloroquine on 
inhibition of the SARS-CoV-2 virus in African green monkey kidney VeroE6 cells.11 They 
evaluated the dose-response curve for chloroquine and hydroxychloroquine across a range of 
multiplicities of infection (MOI) (ratio of viral particles to cells) of SARS-CoV-2 (0.01, .02, 0.2, 
and 0.8) and concentrations of drug (0-50 µM) (Figure 3.4.1). Efficacy was measured using 
quantification of cell copy numbers 4 hours post-infection. Across the MOI range, the 50% 
maximal effective concentration (EC50) of hydroxychloroquine were 4.51, 4.06, 17.31 and 
12.96µM.  The ECs50 for chloroquine were similar across the range, although chloroquine 
appeared to have a lower EC50 for MOI=0.2. Strikingly, the selectivity index (50% cytotoxic 
concentration / 50% effective concentration) was 55 and 61 at MOI 0.01 and 0.02, respectively, 
but decreased to 14.41 and 19.25 at higher concentrations of 0.2 and 0.8. Thus 
hydroxychloroquine may be more effective earlier in the disease, when the concentration of viral 
particles is low. Dosages of hydroxychloroquine 5-6.5mg/kg/day yield blood concentrations of 
approximately 500 ng/ml, or equivalently 1.15 µM, but concentrations in the tissue - particularly 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 12 of 60 
 
 
 
 
the lungs - can reach 200-700x the blood concentration in the steady-state. Similarly, Wang and 
colleagues identified an EC50 for chloroquine of 1.13 for an MOI of 0.05.9  Based on this data, the 
proposed dosing of 400 mg daily will provide a concentration that is efficacious for SARS-CoV- 
2. 
 
Additionally, hydroxychloroquine 400 mg daily is an FDA approved dose for the treatment of 
rheumatoid arthritis and systemic lupus erythematosus. The safety of long-term administration, 
over a time-frame of months to years, is well studied in the rheumatologic population. These 
experiences suggest hydroxychloroquine has a favorable safety profile at a 5-6.5mg/kg/day 
dose level for a period of months to years. 
 
Figure 3.4.1: In vitro viral inhibition dose response curves. 
 
 
 
3.6 Rationale for Duration of Hydroxychloroquine Prophylaxis 
 
The SARS-CoV-2 pandemic has resulted in this virus being endemic in the New York/New 
Jersey region.  Patients undergoing radiation therapy are at increased exposure risk due to daily 
visits to waiting rooms, therapy machines, and frequent clinic visits for up to 7-weeks of daily 
radiation.  Indeed, the SARS-CoV-2 experience in China reports that 41.3% of admissions are 
due to hospital-acquired transmission.17   Thus the daily medical visits required for radiation 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 13 of 60 
 
 
 
 
treatment administration also place cancer patients at significant risk of viral exposure.  Our 
proposed trial attempts to mitigate infection risk through prophylactic use of hydroxychloroquine. 
 
The principle of prophylactic use of hydroxychloroquine for cancer patients is analogous to its 
use in chemoprophylaxis of falciparum malaria, in which travelers to regions where malaria is 
endemic take chloroquine during travel and 2-4 weeks post exposure.18    Similarly, cancer 
patients undergoing radiation are subject to repeat viral exposure risks with every visit.  Given 
that patients are at risk of infection until their last fraction of radiation, and that the viral 
incubation period ranges from 3-14 days - we propose use of prophylactic hydroxychloroquine 
use during radiation therapy as well as 14 days after for potential post-exposure prophylaxis.19 
 
3.7 Hydroxychloroquine in combination with radiation and chemotherapy in cancer 
 
Rosenfeld et al. reported a phase I/II trial of hydroxychloroquine with radiation and 
temozolomide for glioblastomas. The phase I portion used a 3+3 design with escalating oral 
doses from 200 mg to 800 mg in 200 mg increments. 3/3 subjects treated at the 800mg dose 
developed dose-limiting toxicity, primarily in the form of grade 3 neutropenia and 
thrombocytopenia, including 1 patient who developed sepsis. None of 3 patients treated at the 
600 mg phase I level developed a grade 3 toxicity. In the phase II expansion, which included 75 
patients treated with 600 mg by mouth once daily, the risk of grade 3 and 4 thrombocytopenia 
and neutropenia was 15%, which is similar to what is observed in standard practice without 
hydroxychloroquine. This study also describes pharmacokinetics of hydroxychloroquine at 600 
mg by mouth once a day which is in keeping with what is expected in patients treated with 
rheumatologic conditions. The radiotherapy was tolerated with expected toxicities.20 
 
Eldredge et al. conducted a phase I clinical trial of chloroquine (250mg daily) with concurrent 
whole brain radiotherapy. Radiotherapy was given to a total dose of 37.5 Gy in 2.5 Gy daily 
fractions, which is an equivalent dose of 41.25 Gy when given in 2 Gy fractions. The authors 
noted no grade 3 or greater toxicities during treatment, and no greater than expected skin 
toxicity, neurocognitive toxicity, or radiation necrosis.21 
 
Hong et al. treated 50 patients on a phase II study of hydroxychloroquine 400 mg by mouth 
twice daily with short-course chemoradiation (5 Gy x 5  vs. 3 Gy x 10) with concurrent 
capecitabine 825mg/m2  BID, followed by surgical resection and adjuvant gemcitabine. The 
investigators found the hydroxychloroquine to be well tolerated, without a meaningful impact on 
disease-free survival.22 
 
Rangwala et al. treated 40 patients on a phase I protocol of dose-dense temozolomide with 
increasing doses of hydroxychloroquine ranging from 200mg to 1200mg daily. No MTD was 
reached for hydroxychloroquine  and the authors recommended a dosage of 600mg twice daily. 
Importantly, the dose-dense schedule of temozolomide in this study was intermittent, which may 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 14 of 60 
 
 
 
 
explain why treatment with higher doses of hydroxychloroquine were tolerated than in the study 
by Rosenfeld and colleagues. The most common toxicities observed in this group were grade 2 
fatigue (55%), anorexia (28%), nausea (48%), constipation (20%), and diarrhea (20%). 
Treatment up until 400mg of hydroxychloroquine was relatively well tolerated with lymphopenia 
being the primary toxicity (3/7), as would be expected with dose-dense temozolomide.23 
 
Goldberg et al. treated 27 patients with non-small cell lung cancer in a 3+3 phase I dose- 
escalation study with hydroxychloroquine  with or without erlotinib. Hydroxychloroquine  was 
given at 400mg, 600mg and 1000mg dose levels. Grade 3+ toxicities on this trial were 
uncommon, and none were considered related to hydroxychloroquine. No DLTs were observed 
in either arm, so the maximum tolerated dose was 1000mg of hydroxychloroquine.24 
 
Boone and colleagues conducted a phase I/II  trial of hydroxychloroquine (1200mg/day) and 
gemcitabine (1500mg/m2) as neoadjuvant therapy for pancreatic cancer. 35 patients were 
enrolled, and no dose-limiting toxicities were observed.25  The same investigators performed a 
subsequent randomized controlled trial of nab-paclitaxel (1000mg/m2) and gemcitabine 
(125mg/m2) alone, with or without hydroxychloroquine (600mg twice daily) from day 1 until the 
day before planned. The investigators randomized 64 patients (30 chemo alone, 34 chemo + 
hydroxychloroquine). No differences in toxicity were identified, and the authors identified higher 
rates of partial pathologic response (55.9% for chemo + hydroxychloroquine vs. 10% for chemo 
alone), and near complete response (20.6% in chemo + hydroxychloroquine vs. 0% for chemo 
arm). Treatment with hydroxychloroquine  was associated with increased evidence of autophagy 
and tumor immune infiltration in the resection specimens.26 Similarly, Karasic and colleagues 
reported on 112 patients randomized to gemcitabine/nab-paclitaxel +/- hydroxychloroquine 
600mg twice daily. Hydroxychloroquine  was associated with higher neutropenia (42.6% vs. 
22.6%), fatigue (7.4% vs. 0%), nausea (9.3% vs. 0%), peripheral neuropathy (13.0% vs. 5.7%), 
visual changes (5.6% vs. 0%), and neuropsychiatric symptoms (5.6% vs. 0%).27 
 
Chloroquine and hydroxychloroquine have been studied extensively using in vitro studies of 
cancer as inhibitors of autophagy, as well as modifiers of the radiation treatment effect. Clinical 
data in human subjects is more sparse, but several phase I and II trials have been performed 
that have evaluated the safety of combining hydroxychloroquine with chemotherapy, 
radiotherapy, and chemoradiotherapy. The dose-limiting toxicities of hydroxychloroquine or 
chloroquine in these settings has primarily been related to cytopenias, which have primarily 
been observed with very high doses of hydroxychloroquine (600 - 1200 mg per day). Given the 
limited amount of bone marrow that is included in modern radiation fields and the low proposed 
dose of hydroxychloroquine,  we do not expect significant excess toxicities with this approach. 
 
3.7 Risk of Infection Over Time 
For the purpose of this trial, we estimate that among radiotherapy patients in the New York City 
Metropolitan area who do not have a history of SARS-CoV-2 infection or suspected SARS-CoV- 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 15 of 60 
 
 
 
 
2 infection, 40% will become symptomatically infected with SARS-CoV-2 over a course of 
fractionated radiotherapy. Predictions are variable with large confidence intervals, and there is 
significant uncertainty due to dependencies on government actions related to social distancing 
and testing. 
 
As of 3/26/2020, New York state had 33,033 confirmed cases, 1,603 hospitalized cases with 
366 deaths, for a hospitalization rate among confirmed cases of approximately 15% in the 
general population.28   These data fit an exponential model (log10  transform, least squares 
regression R2=0.98). In such a model, the population risk increases from approximately 1% to 
20% over the course of a week, and increases from 20% to 100% over the course of another 
week (Figure 3.7.1). 
 
 
Figure 3.7.1 Exponential Model of Confirmed Cases in New York state over 5 weeks (Data 
from https://covidtracking.com/data) 
 
At the time of this writing, mandatory social distancing is in effect, which may “flatten the curve”. 
In the Chinese experience with strict police enforcement and testing, the peak in detected cases 
did not occur until 1 week after lockdown, and approximately half of the new cases occurred 
after lockdown.29  Further, New York state does not have a true lockdown, but rather a “PAUSE” 
policy which may not be as effective as strict cordon sanitaire as was implemented in Wuhan, 
Hubei Province, China. Thus, despite efforts to reduce the number of new infections, the risk of 
becoming infected over 2-7 weeks of daily radiotherapy likely exceeds 40%.13  (Figure 3.7.2) If 
social distancing is effective at reducing infection rates, as it has been in some countries, the 
pattern of infections may become more cyclical.30 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 16 of 60 
 
 
 
 
 
 
 
Figure 3.7.2. Pattern of COVID-19 diagnoses in early 2020 from Wu et al., JAMA 2020.29 
Timeline of confirmed COVID-19 cases in China (yellow) and the corresponding dates of 
symptom onset (blue).On Jan 22, 2020, the Hubei government declared a class 2 response to a 
public health emergency, leading to restricted travel and enforced social distancing. The rate of 
new symptomatic cases decreased rapidly thereafter (blue), but the peak of diagnosed cases 
(yellow) did not occur until several days later. 
 
Direct estimates on the risk of SARS-CoV-2 infection in this population are not yet available, but 
the infection risks among healthcare providers may provide a reference for the risk of infection 
among cancer patients receiving radiotherapy. Radiotherapy patients are treated on a daily 
basis over the course of several weeks. In addition to time spent in the radiotherapy clinic, they 
may also require supportive care, hydration, amongst other appointments. They may spend 
significant time in shared spaces with other patients, such as waiting areas, cafeterias, or locker 
rooms, or may share equipment, such as X-ray machines, CT scanners, hospital chairs. All of 
these exposures place them at high risk of exposure to SARS-CoV-2 from other patients and 
staff.  Compared with healthcare providers, radiotherapy patients are often older and have 
compromised immune systems from cancer and cancer-related treatment. Unlike healthcare 
providers, cancer patients do not have access to personal protective equipment. 
 
The rate of infection with SARS-CoV-2 is high amongst front-line healthcare providers out of all 
studied groups. In China, 3,300 healthcare providers developed confirmed SARS-CoV-2.31  In 
Italy, 20% of all confirmed infections were in healthcare providers, despite comprising a far 
smaller proportion of the population (4.6%).6  Wang et al. found the attack rate (number of new 
cases in a population at risk / number of people in that population) per day was 3.5 times higher 
in healthcare workers compared to the general population (Figure 3.7.3).32  Furthermore, the 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 17 of 60 
 
 
 
 
authors estimate that at least 59% of true infections were not diagnosed (Figure 3.7.4), 
suggesting that a much larger proportion of healthcare workers were infected. Li and colleagues 
estimated that nearly 86% of cases were not documented, and therefore not reported in official 
statistics.33 Together, these data suggest that nearly 50% of healthcare workers could be 
infected over the course of a few months. 
 
 
Figure 3.5.3 Attack rate of SARS-CoV-2 by sex and healthcare worker status (A) and age (B) 
over different periods during the Chinese Wuhan epidemic. (Figure from Wang et al. MedRxiv 
preprint)32 
 
 
Figure 3.7.4 Laboratory confirmed cases vs predicted number of unconfirmed cases in China 
based upon epidemiologic modeling suggests that confirmed cases represent a small fraction of 
total infections.(Figure from Wang et al. MedRxiv preprint)32 
 
Radiotherapy patients may face similar rates or potentially greater rates of infection compared  
to healthcare workers, since they face similar daily exposures, but are older, have compromised 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 18 of 60 
 
 
 
 
immune systems, and lack personal protective equipment. Whereas the large majority of 
younger patients are asymptomatic or only mildly symptomatic, the proportion of deaths and 
severe cases among older patients and those with comorbidities suggests this proportion will be 
much higher in our cancer population. For instance, in a long-term care center in Washington 
State, USA, 81/120 (67.5%) of residents, with median age of 81 (range 54-100) and 34/180 
(18.9%) of employees were diagnosed with COVID-19 by 3/9/2020. Among 120 residents, 
56.8% were hospitalized and 27.2% died. Early genomic-epidemiologic studies suggest that 
these infections developed over an approximately 2-month period between January and March 
2020.34 
 
Based on these data, we estimate that the true risk of symptomatic infection over 9 weeks for a 
patient who tests negative at enrollment will be at least 40%. This estimate is in keeping with 
estimates from the governmental organizations including California, New York, and Germany.35, 
36 
 
 
3.8 Estimate of effect size for hydroxychloroquine 
There are no known estimates of effect size for hydroxychloroquine for COVID-19 prophylaxis, 
and the available evidence is limited to in vitro data and data in patients who are acutely ill with 
COVID-19. Given in vitro data showing efficacy at lower MOI, we hypothesize that 
hydroxychloroquine will prevent 50% of infections, reducing the infection rate from 40% to 20%. 
 
3.9 Rationale for use of SARS-Cov-2 PCR, Rapid Standard COVID-19 Antigen and 
Serology tests 
 
Rationale for use of SARS-CoV-2 RT -PCR and Rapid Standard COVID-19 Antigen testing: 
SARS-CoV-2 nucleic acid RT-PCR is currently the standard method of diagnosis of active 
infection, and RT-PCR is a standard method used in diagnostic virology.37   Respiratory tract 
specimens are obtained from nasopharyngeal swabs, induced sputum, or bronchoalveolar 
lavage, and RNA is subsequently extracted for amplification. In January 2020, Corman et al. 
published a validated diagnostic workflow evaluating n=297 clinical samples, demonstrating a 
sensitivity of up to 3.8 copies per reaction with a 95% detection probability, with high specificity 
and no cross reaction with other evaluated viruses.37   However, there are several assays used 
across institutions internationally with a range of sensitivity/specificities, and there have been 
reports of sensitivity issues due to inadequate nasal swabs, cross -reactivity against SARS-CoV- 
1, and concerns with regard to the limit of detection.  Concerns regarding sampling are due to 
concern that viral load in the upper respiratory tract is lower than in lower respiratory tract and 
variable amount of viral shedding at different stages of infection.38 
 
MSKCC utilizes a validated, CLIA certified RT-PCR for SARS-CoV-2.   However, in the setting 
of resource shortages (including personal protective equipment for staff obtaining respiratory 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 19 of 60 
 
 
 
 
samples and test kit/reagent availability) we will follow MSKCC COVID-19 testing policy and 
only test when available and appropriate. 
 
The commercial rapid antigen test in this protocol utilizes a nasopharyngeal or oropharyngeal 
swab specimen and is a chromatography based immunoassay.  If present in the specimen, 
extracted antigen binds to anti-COIVD-19 IgG antibody conjugated with color particles in the test 
device. The assay result can be read in 30 minutes, allowing for rapid assessment of active 
SARS-CoV-2 infection. A swab is included in the test kit.  Similar to the RT-PCR for SARS-CoV- 
2 test where PPE is required, we will only administer this test when we have the appropriate 
PPEs so that we do not pose an infection risk for our staff.  This test is also optional and 
dependent on institutional resources. 
 
Rationale for use of SARS-CoV-2 Serology:  Standard Q COVID-19 IgM/IgG rapid 
immunochromatographic  test or Validated Assays  by MSKCC Laboratory Medicine 
While SARS-CoV-2 RT-PCR is the current standard for measuring active infection, it relies on 
expression of viral RNA and is not a reliable method of evaluating prior infection. Serologic 
assays, such as ELISAs and lateral flow immunoassays detect IgM and IgG antibodies against 
the SARS-CoV-2 virus in patient serum. Quantification of IgM and IgG can also help to 
distinguish between the acute and convalescent phase following SARS-CoV-2 exposure, and 
thus also potentially give additional data with regard to long-term immunity.  Therefore, the 
benefit of these serologic tests is that the presence of antibodies to SARS-CoV-2 can indicate 
prior exposure, give data with regard to current immunity, as well as identify asymptomatic 
carriers, and diagnosis patients with symptomatic infection who have mounted an immune 
response. While these assays are standardly used in virology, the assays specific for SARS- 
CoV-2 are currently being validated.39     Zhao et al. reported results from serial plasma samples 
obtained from n=173 patients with symptomatic SARS-CoV-2 infection.  Significantly, 93% of 
patients had an IgA, IgM, or IgG antibody seroconversion rate in n=173 patients, with nearly 
100% seroconversion of total antibody 1 mo after onset of illness, where as <40% of patients 
did in the first 7 days of illness.40 Thus this data indicates that the assay has excellent sensitivity 
>7 days after symptom onset. 
 
MSKCC’s department Laboratory Medicine is currently validating several serologic assays. 
However given that this resource will be limited, in this trial we have another optional  
commercial serology test, the Standard Q COVID-19 IgM/IgG  rapid immunochromatographic 
test ,manufactured by SD Biosensor and distributed to us for the trial by Henry Schein Inc.  The 
serologic assay allows for rapid testing of SARS-CoV-2 IgM and IgG antibodies within 15 
minutes, using 10 uL of whole blood, serum, or plasma.39   This product is registered with the 
FDA  and has a sensitivity of 81.8% and Specificity of 96.6% in all patients tested, as well as 
92.2% sensitivity and 96.6% specificity in specimens tested 8-10 days after the date of symptom 
onset.  We will utilize this rapid serology test to evaluate for prior SARS-CoV-2 exposure in 
combination with clinical assessment of patient symptoms at the time of enrollment. If a patient 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 20 of 60 
 
 
 
 
becomes symptomatic during the trial, we will follow MSKCC guidelines for testing for 
symptomatic patients.  We will also obtain Standard Q COVID-19 IgM/IgG  rapid 
immunochromatographic test and when there is available PPE that does not interfere with 
institution resources, we will obtain the  rapid antigen test.  These tests can be utilized as 
confirmatory tests for our primary endpoint, but are optional and are dependent on available 
institutional resources.  . 
 
Initial serology will enable identification of patients who had prior exposure to the SARS-CoV-2 
virus, who subsequently seroconverted. With pre- and post serology data in patients who 
provide optional research laboratory, we will be able to answer several key questions: 1) 
whether patients who do not develop symptomatic COVID-19 during the trial can seroconvert, 
and 2) how this is influenced by hydroxychloroquine vs. placebo. 
 
Rationale for Optional Research CT Chest Imaging: 
Due to a shortage of test kits during the outbreak in Wuhan, China, diagnoses of COVID-19  
were rendered based upon clinical suspicion and CT chest. Characteristic CT changes 
associated with COVID-19 have previously been described,41  and vary relative to the time frame 
relative to symptom onset as well as the severity of illness.42, 43 In some cases, CT changes may 
precede RT-PCR.44 
 
 
Figure 3.9.1 In a subset of patients with initially negative RT-PCR who subsequently developed 
a positive RT-PCR, most patients had suspicious CT findings on their original CT Chest.44 
 
Studies from China suggest that CT Chest has high sensitivity for COVID-19, but low specificity 
when using RT-PCR as a reference. Because RT-PCR also has limited sensitivity, especially 
early in the disease course, many “false positive” CT scans may actually reflect a false negative 
RT-PCR test. Fang et al. reported on a series of 51 patients who were diagnosed with COVID- 
19 by RT-PCR who had CT Chest within 3-days of diagnosis. Within this hospitalized, 
symptomatic cohort, the sensitivity of CT imaging of the chest was 98%, compared with 71% for 
initial RT-PCR. All patients were eventually diagnosed with COVID-19 by RT-PCR. The average 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 21 of 60 
 
 
 
 
time from symptom onset to testing was 3 +/- 3 days for both RT-PCR and CT Chest.45 In a 
separate study from Wuhan, Ai et al. reported on a series of 1014 cases who underwent both 
CT Chest and RT-PCR for SARS-CoV-2. Using RT-PCR as a reference, the sensitivity of CT 
Chest was 97% and the specificity was 25%, with an overall accuracy of 25%. Interestingly, of 
308 patients with initially negative RT-PCR based on oropharyngeal swab, 81% of were 
subsequently felt to have likely or probable COVID-19 with a false negative on initial RT-PCR.44 
 
The diagnostic performance of CT chest is strongly dependent on the time from treatment 
onset. Wang and colleagues reported a longitudinal radiographic study of 90 patients who 
underwent a cumulative 366 CT scans during their hospitalization for COVID-19. Among 10 
scans that were obtained on the day of symptom onset, 60% were normal. However, the 
percentage of normal scans in confirmed SARS-CoV-2 cases decreased to approximately 14% 
for scans obtained 1-5 days after symptom onset. <5% of scans were normal 6-11 days after 
symptom onset. 
 
Due to concerns regarding a resource shortage, an optional research CT Chest will help to 
establish a baseline for future comparison. Given that part of our cancer workup often times 
includes a baseline CT chest, we do not require additional chest CTs at baseline strictly for the 
purpose of this trial. Due to the relatively high sensitivity, patients with symptoms and a positive 
CT Chest will be excluded from the study. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 Design 
This is a randomized (1:1), double-blind, placebo-controlled phase II clinical trial in subjects ≥18 
years old scheduled to receive at least 10 radiation treatments. Patients undergoing  
neoadjuvant radiation, adjuvant radiation, definitive radiation alone, and chemoradiation are 
eligible.  Subjects will be randomized to either prophylactic hydroxychloroquine or placebo. The 
study will be conducted at Memorial Sloan Kettering (inclusive of Memorial Hospital, MSK 
Bergen, MSK Westchester, MSK Monmouth, MSK Basking Ridge, MSK Nassau, MSK Koch, 
and MSK Commack). Proton therapy is permitted for this protocol at ProCure and NYPC. The 
study will enroll 132 patients meeting the outlined inclusion and exclusion criteria with a planned 
expansion to 166 patients if there is rapid accrual in the first 28 days. 
 
4.3 Intervention 
 
4.3.1. Baseline Assessment 
All patients will undergo baseline history, electrocardiogram, SARS-CoV-2 symptom screen as 
per standard MSKCC policy (Appendix 18.2), and laboratory studies as part of an initial 
assessment for protocol eligibility.   Telemedicine visits are permitted; the baseline physical 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 22 of 60 
 
 
 
 
exam is optional.  Baseline QTc intervals will be calculated from the diagnostic EKG. All patients 
will provide consent. Remote consent is permitted to reduce exposure risks. 
 
Testing capabilities for SARS-CoV-2, demand on laboratory medicine resources, and demand 
on healthcare system resources are in flux, and tests may become unavailable during the 
course of the study. Therefore, we have obtained additional rapid Standard Q COVID-19 
IgM/IgG  rapid immunochromatographic test kits manufactured by SD Biosensor and distributed 
to us for the trial by Henry Schein Inc. If resources are available, patients are recommended to 
undergo negative Standard Q COVID-19 IgM/IgG  rapid serologic testing.   If rapid IgM/IgG 
serology is negative, patients will also undergo rapid standard COVID19 Antigen test if MSKCC 
resources allow (see Section 4.2.2) .  Use of these assays will be optional, and also be 
dependent upon institutional resources. 
 
4.3.2. SARS-CoV-2 PCR Testing and rapid Standard COVID19 Antigen test 
● Patients who develop symptoms during the protocol will be referred for SARS-CoV-2 
PCR testing per MSKCC policy. Testing requirements are subject to change per MSKCC 
policy. We will adhere to MSKCC policy.  When possible, these patients will also  
undergo a Standard Q COVID-19 Ag test. 
● For MSKCC COVID-19 PCR: This assay will only be conducted in accordance with 
MSKCC guidelines and only if PPE resources are available.   A nasopharyngeal swab 
will be collected. Specimens will be stored at 2-8 degrees C for up to 72 hours after 
collection. They will be shipped to Memorial Sloan Kettering Laboratory Medicine on an 
ice pack, per MSKCC SARS-CoV-2 CLIA certified testing protocol. Samples will be 
processed and RNA will be extracted. RNA will be reverse transcribed into cDNA and 
amplified through a real-time PCR instrument. Probe will anneal to a target sequence 
located between forward and reverse primers. Taq polymerase will degrade the probe, 
and the fluorescent signal will be generated by separation of the reporter and quencher 
dye. Fluorescent intensity will be monitored during each cycle and compared to 
housekeeping gene expression. Detection of viral RNA will be determined based on a 
predetermined expression threshold. 
● For STANDARD Q COVID-19 Antigen test: A nasopharyngeal or oropharyngeal 
specimen will be collected using a sterile swab.  The swab with collected specimen will 
be inserted into an extraction buffer tube and swirled at least five times.  The swab is 
removed while squeezing the sides of the tube to extract the liquid from the swab.  The 
filter cap will be screwed onto the tube.  4 drops of extracted specimen from the tube will 
be dropped into the test device.  The test result will be read in 30 minutes per the 
package instructions.  Antigen testing will only be done if PPE resources are available. 
 
Patients who develop COVID-19-like symptoms (as defined by MSKCC Screening criteria), and 
test positive for COVID-19 IgM/IgG  by the rapid serology assay, or test positive for the rapid 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 23 of 60 
 
 
 
 
COVID19 Antigen test, or who test positive forSARS-CoV-2 by PCR, at an outside facility will be 
declared positive for SARS-CoV-2 and will not reflexively be referred for repeat SARS-CoV-2 at 
MSKCC.  All MSKCC COVID-19 PCRs will only be done according to policy.  COVID-19 
serology assays and antigen testing will be done only if institutional resources permit. 
 
Furthermore, given the possibility of resource constraints, we will follow MSKCC policy which is 
subject to change on which patients are considered positive for SARS-CoV-2. 
 
See section 4.2.9 for management of patients who test positive for SARS-CoV-2 by RT PCR or 
Rapid antigen test. 
 
4.3.3. SARS-CoV-2 Serologic Testing 
Optional serology testing will be done at two points for each patient using the qualitative Henry 
Schein Standard Q COVID-19 IgM/IgG  Rapid Test: 
● Initial enrollment for all patients (optional testing) 
● Optional second time point will be one of the following: 
○ 8-20 days after patients on-treatment develop symptoms concerning for COVID- 
19 and are presumed positive per criteria specified in the protocol 
○ 9 weeks following treatment if a patient never develops symptoms concerning for 
COVID-19 during prophylaxis 
● Collection of capillary whole blood specimen: Using a capillary tube, 10 microliters of 
capillary whole blood will be collected through a finger prick.  The collected whole blood 
will be added to the test device well.  3 drops (90 microliters) of buffer will be placed into 
the test device.  Tests will be read in 10-15 minutes.  Tests will be interpreted as positive 
if IgM and/or IgG is detected. 
 
Research correlative serum (optional) will be collected at two points for each patient for analysis 
in our correlative objectives seeking to quantify SARS-CoV-2 IgG/IgM in validated ELISA at 
MSKCC.  Serology will be banked and will not be processed immediately by laboratory medicine 
to conserve resources: 
● Initial enrollment for all patients 
● Second time point will be one of the following: 
○ 8-20 days after patients on-treatment develop symptoms concerning for COVID- 
19 and are presumed positive per criteria specified in the protocol 
○ 9 weeks following treatment if a patient never develops symptoms concerning for 
COVID-19 during prophylaxis 
 
Processing of research serum: 8-10 mL of whole blood will be aseptically collected in a serum 
separator tube.  Blood will be allowed to clot for 30 minutes at room temperature and the  
sample will be centrifuged at 2000g for 10 minutes in a 4 degrees C centrifuge.  The 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 24 of 60 
 
 
 
 
supernatant (serum) will be immediately transferred into a sterile polypropylene tube.  Samples 
can be maintained at 2-8 degrees C for <48 hours while awaiting transport.  Samples will be 
banked in aliquots at -20 degrees C for future analysis in collaboration with MSKCC Laboratory 
Medicine. 
 
4.2.5. Randomization Timing Instructions 
Following enrollment patients will undergo randomization to placebo or hydroxychloroquine as 
outlined in Section 7.  For patients who have not yet started radiation, randomization will take 
place no greater than 2 business days prior to radiation treatment start. Patients who develop 
COVID-19 symptoms (Temp >38.0C in addition to sore throat, cough, shortness of breath, 
wheezing, chest tightness, body aches/myalgias,  or chills, diarrhea, or anosmia) after 
enrollment but prior to randomization will need to undergo repeat assessment (SARS-CoV-2 
serology, antigen testing, or PCR)  before starting hydroxychloroquine.  We will adhere to the 
MSKCC screening guidelines.  These guidelines are subject to change and we will add any 
additional new screening guidelines to this protocol.  For patients who have already started 
radiation at the time of enrollment, randomization will take place immediately after enrollment. 
Patients, providers, and clinical research staff will be blinded to the randomization. 
Randomization will occur 2 business days prior to the first fraction of radiation.  For patients who 
have already started their radiation treatment course at the time of enrollment, please note  
again that there must be enough fractions remaining in their treatment course to allow for a 
minimum of 10 fractions with hydroxychloroquine or placebo after randomization to be eligible  
for this trial. 
 
4.2.6. Drug administration 
Hydroxychloroquine  will be administered at a weight-based dose: 
● Weight ≥ 60 kg: 400 mg daily (7 days/week) administered in 2 tablets, 200 mg/tab 
● Weight <60 kg: 
○ Mon, Wed, Fri, Sun: 400 mg daily administered in 2 tablets, 200 mg/tablet 
○ Tues, Thurs, Sat: 200 mg daily administered in 1 tablet, 200 mg/tablet 
 
Dose reduction to 200 mg daily (7 days/week) will be done for patients with Grade 3 renal or 
hematologic adverse events, until the toxicity has resolved to grade 1.  These dose reductions 
are safety measures as hydrochloroquine is renally excreted and immunomodulatory.  If 
randomized to placebo, patients will be given an equivalent number of weight-based placebo 
tablets.  In the event that the patient is unable to swallow the tablets (i.e. due to dysphagia, PEG 
dependence), MSKCC pharmacy will provide an oral suspension of equivalent dosage.  See 
Section 10.3.2 for details on drug or placebo administration. 
 
For patients who have not yet started radiation therapy at the time of enrollment, drug 
administration will start on the same day as the first fraction of radiation.  For patients who have 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 25 of 60 
 
 
 
 
started radiation therapy at the time of enrollment, drug administration will start upon receipt, 
such that there are a minimum of 10 radiation treatments concurrent with hydroxychloroquine. 
Treatment with daily (7 days/week) hydroxychloroquine or placebo, as per randomization, will 
continue for the duration of radiation therapy for all patients and continue for 14 days after the 
completion of radiation therapy. A weekly supply of drug or placebo will be provided to patients 
at MSK pharmacies. The patient will continue the drug until they test positive by SARS-CoV-2 
criteria or meet positive criteria as determined in Section 13.1.  If there are radiation treatment 
interruptions ≥ 3 days, for non-COVID-19 related reasons the drug or placebo will be held.  The 
study drug/placebo will be self-administered by the patient.  Subjects will not be monitored 
during dose administration. A medication diary will be provided for the patient to document self- 
administration. 
 
4.2.7. Radiation therapy: 
Standard radiation therapy will be prescribed and administered as per the patient’s radiation 
oncologist.  Eligible radiation therapy regimens for patients who have not started radiotherapy at 
the time of enrollment regimens consist of a minimum of 10 fractions.  Patients who are already 
undergoing radiation therapy at the time of the start of treatment for this protocol must have at 
least 10 remaining radiation fractions following enrollment and randomization, such that 
hydroxychloroquine is administered with 10 radiation treatments.  Neoadjuvant, definitive, 
adjuvant, palliative, and hypofractionated regimens are allowed as long as the number of 
fractions meets the aforementioned requirements.  Fractions in the radiation course can be 
administered daily, every other day, or twice daily as long as the number of fractions meets the 
aforementioned requirements.  Radiation therapy will be performed with external beam ionizing 
radiation as per standard of care in accordance with institutional practice. Proton therapy is 
permitted for this protocol at ProCure and NYPC. At the time of CT simulation, the CT will 
include the entire thorax with breath hold and thin cuts, as protocoled in conjunction with 
Radiology and Radiation Oncology.  The radiation simulation order will specify that the patient is 
enrolled on a clinical trial, and under simulation comments the following language should be 
included: “Extend CT simulation to include thorax, breath hold, thin cuts.  No additional contrast 
or immobilization needed.”   Dose to targets and organs at risk must be minimized and must 
satisfy institutional guidelines.  Image guidance will be at the discretion of the treating radiation 
oncology in accordance with institutional practice.  Patients who screen positive based on 
MSKCC symptom criteria and/or test positive on SARS-CoV-2 PCR or serology test - will have 
their radiation treatment course determined per department guidelines (Appendix  18.2). 
Radiation treatments may be either with proton radiotherapy or standard radiotherapy. 
 
4.2.8. Chemotherapy: 
The addition of concurrent chemotherapy to radiation will be determined by the patient’s medical 
oncologist as per standard of care and disease management team practice at MSKCC. Biologic 
agents and immunotherapy given concurrently with radiation must be in line with MSKCC 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 26 of 60 
 
 
 
 
radiation oncology department practice.   Standard of care laboratories associated with the 
patient’s chemotherapy regimen will be obtained as per the patient’s medical oncologist. 
 
4.2.9. Symptom screening and toxicity assessments: 
In addition to the mandated institutional policy for all patients entering an MSKCC building for 
radiation to undergo COVID-19 screen with every treatment, patients enrolled on the trial will 
undergo symptom screening by clinical nursing staff,  the patient’s medical provider, or the 
PI/Co-PIs  (Screening, week 1, and week 12).  This can be done remotely via telemedicine. 
Risk factors and symptoms associated with SARS-CoV-2 will be assessed through the 
Screening and Toxicity form in Appendix 18.1. 
 
Patients will undergo standard of care weekly clinical radiation oncology status checks with 
assessments based on body site as per standard of care at Memorial Sloan Kettering. 
Telemedicine/remote status checks as well as telemedicine-based research screens are 
permitted and encouraged.  Patients must be assessed for initiation of QTC prolonging agents 
(Appendix 18.3).   Principal investigators and research staff should be notified for patients who 
screen positive.  Principal investigators and research staff should be notified for any grade ≥3 
adverse events, QTC>500, if patients are started on any QTC prolonging agents, and hospital 
admissions. 
 
If a patient screens positive for COVID-19, the Principal Investigators must be notified of the 
date of symptom onset, the testing ordered, and the outcomes of the test (SARS-CoV-2 Rapid 
IgM/IgG  serology, COVID-19 Antigen, or COVID-19 PCR, MSKCC Elisa based Serology test). 
The principal investigators should be notified of all hospitalizations or deaths for any reason. 
 
4.2.10. On-treatment or post-treatment SARS-CoV-2 testing: 
Patients who screen positive as defined in Appendix 18.2 will undergo standard MSKCC SARS- 
CoV-2 testing, with sample collection and testing methods as previously outlined.  We will 
adhere to MSKCC policy in the determination of which patients are positive for SARS-CoV-2. 
Patients with negative symptom screens throughout their treatment course will complete a 
course of hydroxychloroquine or placebo (as specified by randomization) for the duration of 
radiotherapy and for 14 days post-radiation, and undergo post-treatment SARS-CoV-2 testing 
as described and following MSKCC policy. 
 
4.2.11. SARS-CoV-2 positive patients: 
Patients enrolled on the trial who test positive for SARS-CoV-2 will no longer continue the study 
intervention, but will continue to be followed for study purposes. Patients who are enrolled on 
trial who develop symptoms suspicious for COVID-19 and who have a positive test for COVID- 
19 prior to randomization will be removed from trial and replaced. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 27 of 60 
 
 
 
 
SARS-CoV-2 infection management will be as per Memorial Sloan Kettering infectious disease 
team standard of care/policy.  The patient’s radiation treatment course will be determined per 
Memorial Sloan Kettering Radiation Oncology Department policy for SARS-CoV-2 positive 
patients. 
 
4.3 Estimated Duration of Subject Participation 
Enrolled patients will be treated with hydroxychloroquine or placebo daily (7 days/week) for the 
duration of radiation therapy plus 14 days after the completion of radiation.  All subjects will be 
followed for SARS-CoV2 infection status, hospitalizations, toxicity, and survival weekly during 
radiation and at 9 weeks after start of drug, unless the patient meets c riteria for trial removal, or 
the Principal Investigator elects to end the study. Patients will be followed for development of 
COVID-19 symptoms, diagnosis of COVID-19, hospitalization (for any reason), critical or 
supportive care, or death.  If a patient develops grade 4 toxicity or is admitted to a hospital, the 
patient’s treatment arm will be unblinded at the discretion of the PI or co-PIs. 
 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS & NON-THERAPEUTIC ASSESSMENTS 
 
5.2 Hydroxychloroquine 
 
5.2.1. Description: 
Hydroxychloroquine sulfate is a white or practically white, crystalline powder, freely soluble in 
water; practically insoluble in alcohol, chloroform, and in ether. The chemical name for 
hydroxychloroquine sulfate is 2-[[4-[(7-Chloro-4-quinolyl)  amino]pentyl]  ethylamino]ethanol 
sulfate (1:1). Its structural formula is: The molecular weight of hydroxychloroquine sulfate is 
433.95, and molecular formula is C18H26ClN3O.H2SO4. Hydroxychloroquine  tablets contain 
200 mg hydroxychloroquine sulfate, equivalent to 155 mg base, and are for oral administration. 
Inactive Ingredients: Dibasic calcium phosphate USP, hypromellose USP, magnesium stearate 
NF, polyethylene glycol 400 NF, polysorbate 80 NF, corn starch, titanium dioxide USP, 
carnauba wax NF, shellac NF, black iron oxide. 
 
5.2.2. Pharmacokinetics: 
Following a single 200 mg oral dose of hydroxychloroquine to healthy males, the mean peak 
blood concentration of hydroxychloroquine was 129.6 ng/mL, reached in 3.26 hours with a half- 
life of 537 hours (22.4 days). In the same study, the plasma peak concentration was 50.3 ng/mL 
reached in 3.74 hours with a half-life of 2963 hours (123.5 days). Urine hydroxychloroquine 
levels were still detectable after 3 months with approximately 10% of the dose excreted as the 
parent drug. Results following a single dose of a 200 mg tablet versus i.v. infusion (155 mg), 
demonstrated a half-life of about 40 days and a large volume of distribution. Peak blood 
concentrations of metabolites were observed at the same time as peak levels of 
hydroxychloroquine. The mean fraction of the dose absorbed was 0.74. After administration of 
single 155 mg and 310 mg intravenous doses, peak blood concentrations ranged from 1161 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 28 of 60 
 
 
 
 
ng/mL to 2436 ng/mL (mean 1918 ng/mL) following the 155 mg infusion and 6 months following 
the 310 mg infusion. Pharmacokinetic parameters were not significantly different over the 
therapeutic dose range of 155 mg and 310 mg indicating linear kinetics. Following chronic oral 
administration of hydroxychloroquine, significant levels of three metabolites, 
desethylhydroxychloroquine  (DHCQ), desethylchloroquine  (DCQ), and 
bidesethylhydroxychloroquine  (BDCQ) have been found in plasma and blood, with DHCQ being 
the major metabolite. The absorption half-life was approximately 3 to 4 hours and the terminal 
half-life ranged from 40 to 50 days. The long half-life can be attributed to extensive tissue 
uptake Reference ID: 4047416 rather than through decreased excretion. Peak plasma levels of 
hydroxychloroquine were seen in about 3 to 4 hours. Renal clearance in rheumatoid arthritis 
(RA) patients taking hydroxychloroquine for at least six months seemed to be similar to that of 
the single dose studies in volunteers, suggesting that no change occurs with chronic dosing. 
Range for renal clearance of unchanged drug was approximately 16 to 30% and did not 
correlate with creatinine clearance; therefore, a dosage adjustment is not required for patients 
with renal impairment. In RA patients, there was large variability as to the fraction of the dose 
absorbed (i.e. 30 to 100%), and mean hydroxychloroquine levels were significantly higher in 
patients with less disease activity. Cellular levels of patients on daily hydroxychloroquine have 
been shown to be higher in mononuclear cells than polymorphonuclear leukocytes. 
 
5.2.3. Supply: 
Hydroxychloroquine  and placebo will be provided by Rising Pharmaceuticals. 
Hydroxychloroquine will be provided in 200mg tablets.  Hydroxychloroquine will be stored, 
prepared, and administered per MSKCC guidelines.  Placebo will be manufactured for the 
purpose of this blinded study with the same size, shape, color, and identification code as the 
hydroxychloroquine.   Placebo will be manufactured with ingredients that constitute 
hydroxychloroquine without the active ingredients.  The investigator shall take responsibility for 
and shall take all steps to maintain appropriate records and ensure appropriate supply, storage, 
handling, distribution, and usage of hydroxychloroquine. 
 
5.2.4. Formulation, Packaging, and Storage 
Hydroxychloroquine tablets are white, to off-white tablets.  Each tablet contains 200 mg of 
hydroxychloroquine.  Dispense in a light-resistant container as defined in USP/NF.  Keep out of 
the reach of children. Store at room temperature, allow excursions between 15 and 30 degrees 
C. 
 
6.1 
CRITERIAFOR SUBJECT ELIGIBILITY 
 
6.2 Participant Inclusion Criteria: 
● Age ≥ 18 
● ECOG 0-3 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 29 of 60 
 
 
 
 
● For patients who have not started radiation at the time of screening: patients are 
required to have a plan in place for a minimum of 10 radiation treatments with or without 
concurrent systemic therapy 
● For patients who have already started radiation at the time of screening: patients must 
complete enrollment such that they are able to receive at least 10 radiation treatments 
with hydroxychloroquine. 
● §Disease Site 
● Mandatory inclusion criteria: 
○ No COVID-19 symptoms within 14 days of enrollment: 
■ (Temp >38C in addition to sore throat, cough, wheezing, chest tightness, 
shortness of breath, body aches, chills, diarrhea, and anosmia) 
■ If symptoms are present within 14 days of enrollment, patients with a 
negative COVID-19 PCR or COVID-19 serology assay are eligible for 
inclusion. 
○ No close contact with confirmed COVID-19 person 
■ Close contact defined as: 
● Within 6 feet for prolonged period 
● Cohabitating 
● Optional laboratory criteria (Recommended if available) 
○ Negative pre-treatment SARS-CoV-2 rapid antigen test result (within 1 week of 
enrollment) 
○ Negative pre-treatment SARS-CoV-2 PCR test result (within 1 week of 
enrollment) using MSKCC laboratory or outside laboratory assay 
○ Negative pre-treatment Standard Q COVID-19 IgM/IgG  rapid serology result 
(within 1 week of enrollment) 
○ Blood serum for SARS-CoV-2 serology tests (being validated by MSKCC) 
 
§Disease site meets following criteria: 
● Head and Neck / High-Risk Skin Cancer 
● Lung Cancer 
● Breast Cancer 
● Prostate Cancer 
● Central Nervous System Tumors 
● Gastrointestinal System Cancer 
● Gynecologic cancer 
● Other disease sites permitted at PI discretion 
 
See section 9.1 for management guidelines regarding discordant RT-PCR and CT Chest criteria 
 
6.3 Participant Exclusion Criteria: 
● Previous positive test for SARS-CoV-2 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 30 of 60 
 
 
 
 
● Previous positive serology test for SARS-CoV-2 
● Recent Chest CT meeting CT exclusion criteria 
● Live in a skilled nursing facility with COVID-19 symptoms (Temp >38 C in addition to 
sore throat, cough, wheezing, chest tightness, shortness of breath, body aches or chills, 
diarrhea, anosmia) 
● Known hypersensitivity to hydroxychloroquine or 4-aminoquinoline derivatives 
● Pre-existing retinopathy 
● Known chronic kidney disease, stage 4 or 5, or receiving dialysis 
● Breast Feeding 
● Tamoxifen 
● Absolute neutrophil Count <1,000/ml at registration 
● Concurrent use of any other quinine derivative 
● Antiarrhythmic medications: amiodarone, sotalol, dofetilide, procainamide, quinidine, 
flecainide 
● Glucose-6-phosphate dehydrogenase  deficiency 
● Pre-treatment corrected QT interval (QTc) ≥470 milliseconds** 
● Prisoners 
● Inability to participate 
● Psoriasis 
● History of suicidal ideation 
 
* CT Criteria for Enrollment Exclusion (Optional - only for patients who received a diagnostic CT 
as part of standard of care or a thoracic CT as part of radiation simulation): 
 
All patients with COVID-19 typical radiographic findings on CT Chest as defined by the RSNA 
will be excluded.  Patients with any NEW COVID-19 indeterminate radiographic findings on CT 
Chest that are concerning for COVID-19 will be excluded.  COVID-19 indeterminate features are 
permitted if they can be demonstrated as STABLE on prior (>14 calendar days) CT Chest or 
PET/CT. If no prior comparison is available AND any intermediate or typical feature is present, 
the patient is not eligible. 
● COVID-19 Atypical Features 
○ Isolated lobar or segmental consolidation without GGO 
○ Discrete small nodules (centrilobular, “tree-in-bud”) 
○ Lung cavitation 
○ Smooth interlobular septal thickening with pleural effusion 
● COVID-19 Indeterminate Features 
○ Multifocal, diffuse, perihilar, or unilateral GGO with or without consolidation 
lacking a specific distribution and are non-rounded or non-peripheral 
○ Few very small GGO with a non-rounded and non-peripheral distribution 
● COVID-19 Typical Features 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 31 of 60 
 
 
 
 
○ Peripheral, bilateral GGO with or without consolidation or visible intralobular lines 
(“crazy paving”) 
○ Multifocal GGO of rounded morphology with or without consolidation or visible 
intralobular lines (“crazy paving”) 
○ Reverse Halo sign or other findings of organizing pneumonia 
 
** If pre-treatment QTC can be decreased to <470, the patient can be re-considered for trial. 
 
7.0 
RECRUITMENT PLAN 
 
Potential research subjects will be identified by a member of the patient’s radiation oncology 
team; the site protocol investigator, or a research team at Memorial Sloan-Kettering Cancer 
Center (MSKCC). If the investigator is a member of the treatment team, s/he will screen their 
patient’s medical records for suitable research study participants and discuss the study and their 
potential for enrolling in the research study. Potential subjects contacted by their treating 
physician will be referred to the investigator/research staff of the study. 
 
The site principal investigator may also screen the medical records of patients with whom they 
do not have a treatment relationship for the limited purpose of identifying patients who would be 
eligible to enroll in the study and to record appropriate contact information in order to approach 
these patients regarding the possibility of enrolling in the study. 
 
During the initial conversation between the investigator/research staff and the patient, the 
patient may be asked to provide certain health information that is necessary to the recruitment 
and enrollment process. The investigator/research staff may also review portions of their 
medical records at MSKCC in order to further assess eligibility. They will use the information 
provided by the patient and/or medical record to confirm that the patient is eligible and to 
contact the patient regarding study enrollment. 
 
In most cases, the initial contact with the prospective subject will be conducted either by the 
treatment team, investigator or the research staff working in consultation with the treatment 
team. This initial contact can be done via a telemedicine visit or telephone encounter.  The 
recruitment process outlined presents no more than minimal risk to the privacy of patients who 
are screened and minimal PHI will be maintained as part of a screening log. For these reasons, 
we seek a (partial) limited waiver of authorization for the purposes of (1) reviewing medical 
records to identify potential research subjects and obtain information relevant to the enrollment 
process; (2) conversing with patients regarding possible enrollment; (3) handling of PHI 
contained within those records and provided by the potential subjects; (4) maintaining 
information in a screening log of patients approached (if applicable), and (5) reviewing CT 
imaging and calling patients to confirm details regarding COVID-related testing, complications, 
or symptoms. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 32 of 60 
 
 
 
 
The limited waiver will apply only to MSKCC. 
 
7.1. Research Participant Registration 
Confirm eligibility as defined in the section entitled Inclusion/Exclusion Criteria. Obtain informed 
consent, by following procedures defined in section entitled Informed Consent Procedures. 
During the registration process registering individuals will be required to complete a protocol 
specific Eligibility Checklist. The individual signing the Eligibility Checklist is confirming whether 
the participant is eligible to enroll in the study. Study staff are responsible for ensuring that all 
institutional requirements necessary to enroll a participant to the study have been completed. 
See related Clinical Research Policy and Procedure #401 (Protocol Participant Registration). 
 
7.2 CRDB Blinded Randomization 
This is a double blind randomized comparison of hydroxychloroquine or placebo. After eligibility 
is established and consent is obtained, patients will be registered through the Clinical Trials 
Management System (CTMS) and then randomized using the Randomization Module in the 
Clinical Research Database (CRDB). Randomization will be accomplished by the method of 
random permuted block, age (>65 vs. ≤ 6 weeks), duration of radiation therapy with concurrent 
hydroxychloroquine or placebo (>4 vs. ≤4 weeks), receipt of concurrent chemotherapy (yes vs. 
no). Since this is a double blind study, the patients’ treatment assignments can be viewed in the 
CRDB only by the hospital pharmacists who are dispensing the study drugs. All data will be 
collected and analyzed at MSKCC. Compiled data will be submitted to the biostatistician on 
study (Dr. Zhigang Zhang) for analysis. 
 
7.3 Breaking the Blind 
At all times, treatment and randomization information will be kept confidential and will not be 
released to the patient, investigator, the study staff, or the sponsor’s study team until following 
the conclusion of the study, with the exception described in this section. 
 
At the initiation of the study, the study site will be instructed on procedures for breaking the  
blind. Blinding codes should be broken only in emergency situations for reasons of patient 
safety. If the patient has an adverse event that may be considered hydroxychloroquine mediated, 
treatment for the adverse event should be administered as if the patient is receiving 
hydroxychloroquine. Whenever possible, the investigator should contact the principal 
investigator before breaking the blind. The method will be either a manual or electronic process. 
When the blind of a patient has been broken, the reason must be fully documented. If the blind 
is broken, the investigator should promptly inform the study PI. The patient for whom the blind 
has been broken will be discontinued from the study treatment. 
 
If a patient develops grade 4 toxicity or is admitted to a hospital, the treatment arm will be 
unblinded at the PI or co-PIs discretion. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 33 of 60 
 
 
 
 
8.1 INFORMED CONSENT PROCEDURES 
 
Before protocol-specified procedures are carried out, consenting professionals will explain full 
details of the protocol and study procedures as well as the risks involved to participants prior to 
their inclusion in the study. Participants will also be informed that they are free to withdraw from 
the study at any time. All participants must sign an IRB/PB-approved consent for indicating their 
consent to participate. This consent form meets the requirements of the Code of Federal 
Regulations and the Institutional Review Board/Privacy Board of this Center. 
The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of the study and the likely follow-up required 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of supportive care 
for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol 
5. The right of the participant to accept or refuse study interventions/interactions and to 
withdraw from participation at any time. 
Before any protocol-specific procedures can be carried out, the consenting professional will fully 
explain the aspects of patient privacy concerning research specific information. In addition to 
signing the IRB Informed Consent, all patients must agree to the Research Authorization 
component of the informed consent form. 
 
Each participant and consenting professional will sign the consent form. The participant must 
receive a copy of the signed consent form. 
 
9.1 
PRETREATMENT  EVALUATION/INTERVENTION 
 
Within 60 days of starting treatment, the following tests need to be done: 
● Complete History 
● Physical Examination (not required) 
● Vital Signs (pulse, blood pressure), including weight 
● Performance Status 
● Record of concomitant medications 
● Signed informed consent (electronic permitted) 
● Electrocardiogram with QTc calculation 
● Comprehensive Panel, including liver function tests (albumin, alkaline phosphatase, total 
bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, potassium, total 
protein, SGOT [AST], SGPT [ALT], sodium). 
● Complete Blood Count (including platelets) 
● G6PD Deficiency testing 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 34 of 60 
 
 
 
 
● Women of childbearing potential must have negative pregnancy test per radiation 
oncology standard of care 
● Research blood draw (this should be performed on the same day as initial SARS-CoV-2 
testing): Peripheral blood samples will be collected in 1 serum separator tube (for 
serologic testing). 
● Optional pre-treatment SARS-CoV-2 testing: IgM/IgG  rapid serology, within 1 week of 
randomization.  The rapid serology test is negative and there are available PPE, a rapid 
Standard COVID19 antigen test will be performed if institutional resources permit. 
● Screening risk assessment for prior COVID-19 infection, COVID-19 household contacts, 
or COVID-19 symptoms (Temp >38C in addition to sore throat, cough, shortness of 
breath, wheezing, chest tightness, body aches or chills, anosmia, diarrhea) within 1 
week of randomization 
 
9.2 Management of patients based on Rapid serology and Antigen testing 
- 
Patients who are COVID-19 IgM and IgG negative when possible should undergo Rapid 
COVID-19 antigen testing to enroll on the trial. 
- 
Patients who are COVID-19 IgM and IgG negative, who then undergo Rapid COVID-19 
antigen testing but are found to be COVID-19 antigen positive will not be enrolled on the 
trial.  Antigen testing suggests active infection and patients will be advised to take safety 
measures as if COVID-19 positive. 
- 
Patients who are COVID-19 IgM and/or IgG positive do not meet criteria for the trial. 
Their serology indicates COVID-19 exposure and out of caution will be advised to take 
safety measures as if COVID-19 positive. 
- 
If at any time during the trial patient is tested with MSKCC COVID-19 PCR for a clinical 
reason, a positive result from the PCR will supersede all point of care serology and 
antigen testing.  Patients in this circumstance will be presumed positive and will either 
not be enrolled on the study or will discontinue study drug. 
- 
All patients who are presumed positive will be managed per MSK Infectious disease 
policy and their radiation treatment course will be in accordance with MSK Radiation 
Oncology Department policy 
 
 
10.1 
TREATMENT/INTERVENTION  PLAN 
 
10.2 Dosing Instructions and Schedule 
 
10.2.1. Hydroxychloroquine Dosing Instructions and Schedule 
Hydroxychloroquine  will be administered at the following weight-based dose: 
● Weight ≥ 60 kg: 400 mg daily (7 days/week) administered in 2 tablets, 200 mg/tab 
● Weight <60 kg: 
○ Mon, Wed, Fri, Sun: 400 mg daily administered in 2 tablets, 200 mg/tablet 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 35 of 60 
 
 
 
 
○ Tues, Thurs, Sat: 200 mg daily administered in 1 tablet, 200 mg/tablet 
● If randomized to placebo, patients will be given the equivalent tabs and schedule, based 
upon weight 
 
For patients who have not yet started radiation therapy at the time of enrollment, drug or 
placebo will be administered within 48 hours of the first fraction of radiation.  For patients who 
have started radiation therapy at the time of enrollment, drug or placebo administration will be 
upon receipt of medication. Hydroxychloroquine or placebo will continue until 14 days after the 
completion of radiation treatments. A weekly supply of drug or placebo will be provided to 
patients.  Drug will be self-administered by the patient.  Subjects will not be monitored during 
dose administration.  A medication diary will be provided for the patient to document self- 
administration and to list daily dosages of medication. 
 
10.1.2 Radiation Dosing Instructions and Schedule 
Radiation therapy will be started after simulation as per MSKCC department timeline.  Patients 
will undergo a standard of care course of radiation at the discretion of the treating radiation 
oncologist.  Radiation dose to target and organs will be in accordance with MSKCC institutional 
guidelines. 
 
10.1.3 Chemotherapy Dosing Instructions and Schedule 
In patients who are receiving chemotherapy, immunotherapy, or biologic therapy with radiation - 
chemotherapy will be as per standard of care in accordance with institutional practice and at the 
discretion of the treating medical oncologist.  Administering concurrent radiation with systemic 
agents must be in accordance with MSKCC radiation oncology department practice. 
 
10.2 Concomitant Medications and Therapies 
 
All medication that is considered necessary for the subject’s welfare, and which is not expected 
to interfere with the evaluation of the study treatment, may be given at the discretion of the 
investigator. 
 
10.2.1 Permitted concomitant therapy includes: 
● Standard therapies for concurrent medical illness 
● Supportive care for any underlying illness 
● Palliative (limited-field) radiation therapy is permitted 
● Treatment with nonconventional therapies (such as acupuncture), and vitamin/mineral 
supplements are permitted provided the therapy does not interfere with the study 
endpoints, in the opinion of the investigator 
● Bisphosphonates or denosumab 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 36 of 60 
 
 
 
 
● Subjects who are therapeutically treated with an agent such as warfarin or heparin will 
be allowed to participate provided that their medication dose and INR/PTT are 
considered stable by the treating physician. 
 
10.2.2. Excluded Concomitant Medications 
Subjects must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the investigator. 
 
The following medications are considered exclusionary during the study. The Principal 
Investigator must be notified if a subject receives any of these during the study. 
● Antiarrhythmic medications: amiodarone, sotalol, dofetilide, procainamide, quinidine, 
flecainide 
 
The study team must document if QT prolonging medications are administered at any time 
during the study period. Efforts should be made to avoid QT prolonging medications if 
acceptable alternatives are available.  See QT prolongation section in 15.7 
 
Precautions should be taken with the following medications listed in Section 15.4.  Patients will 
not be excluded based on these medications but patients will be monitored cautiously with a 
minimum of q2 week laboratory evaluation and weekly symptoms/toxicity screen. 
 
10.3 Hydroxychloroquine Dose Modification and Discontinuation 
 
10.3.1 Initial Hydroxychloroquine  Dose 
● Patients will be initiated on a weight based dose (As outlined 10.1). 
● Patients currently on any medications that have the potential to interact with 
Hydroxychloroquine  (drug interactions) will not undergo dose modifications and will be 
monitored on treatment. 
 
10.3.2. Hydroxychloroquine Dose Modifications and Discontinuation During Treatment 
For subjects who do not tolerate the protocol-specified dosing schedule due to toxicity that is 
relevant to hydroxychloroquine administration or any toxicity that may be impacted by 
hydroxychloroquine, dose modifications and interruptions are recommended in order to allow 
subjects to continue the study treatment. The dose modifications for the hydroxychloroquine- 
specific scenarios (QTc prolongation, acute kidney injury, and cytopenias) are outlined below. 
 
Toxicities will be graded according to CTCAE version 5.0 of the NCI Common Terminology 
Criteria for Adverse Events CTCAE version 5.0 is identified and located on the CTEP website at 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 37 of 60 
 
 
 
 
For subjects who develop QTc prolongation during therapy.  The following hydroxychloroquine 
dose modification guidelines are recommended: 
 
 
 
QTc Prolongation 
Recommended management or dose modification 
QTc>500 msec 
based on an average 
value of triplicate 
ECGs 
-Assess the quality of the ECG, QT value, and repeat if needed 
-Test serum potassium, calcium, phosphorus, and magnesium.  If 
abnormal, correct per routine clinical practice to within normal limits. 
-Review concomitant medication and identify any association with QT 
prolongation*. 
-If a QTc prolonging agent is identified continue hydroxychloroquine 
at the current dose, but withhold the agent if medically feasible and 
recheck QTc in 5-10 days. 
-If persistent QTc >500 msec or if no other QTc prolong agent is 
identified, remove patient from study 
*QTc prolonging medications include: haloperidol, ziprasidone, quetiapine, thioridazine, 
olanzapine, risperidone, amiodarone, sotalol, dofetilide, procainamide, quinidine, flecainide, 
macrolides, fluoroquinolones,  amitriptyline, imipramine, citalopram, methadone, sumatriptan, 
ondansetron, cisapride.  Following trial enrollment will have QTC rechecked 1 week after 
initiation of the QTC prolonging agent.  Notify Principal investigators if QTc prolonging 
medications are initiated after enrollment. 
 
For subjects who develop acute kidney injury during therapy.  The following dose modification 
guidelines are commended: 
 
Grade 
Recommended Management 
Dose modification 
1-2 
-Monitor creatinine weekly 
-If creatinine returns to baseline resume 
routine creatinine monitoring per protocol 
-Promote hydration and cessation of 
nephrotoxic drugs 
Maintain current dose of 
hydroxychloroquine 
3 
-Monitor creatinine every 2-3 days 
-Promote hydration and cessation of 
nephrotoxic drugs 
-Consult nephrology 
Reduce hydroxychloroquine dose to 
200 mg daily and restart at initial dose 
once CrCl recovered or returns to 
Grade 1. 
4 
-Monitor creatinine daily 
-Consult nephrology 
-Promote hydration and cessation of 
-Discontinue hydroxychloroquine  and 
remove from study 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 38 of 60 
 
 
 
 
 
nephrotoxic drugs 
 
For patients who develop cytopenias during therapy.  The following dose modification 
guidelines are recommended. 
 
Grade 
Recommended Management 
Dose modification 
1-2 
-Monitor CBC w/diff weekly 
-Management per medical oncology 
Maintain current dose of 
hydroxychloroquine 
3 
-Monitor CBC w/diff daily-weekly per 
provider discretion 
-Consider holding immunosuppressive 
agents 
-Management per medical oncology 
Reduce hydroxychloroquine dose to 
200 mg daily and restart at initial dose 
once cytopenia returns to Grade 1. 
4 
-Management per medical oncology 
-Consider holding immunosuppressive 
agents 
-Discontinue hydroxychloroquine  and 
remove from study 
 
 
11.1 EVALUATION  DURING TREATMENT/INTERVENTION 
 
11.2 Study Calendar 
 
Study Week (from 
randomization) 
Pre 
Studya 
Wk 
1 
Wk 
2 Wk3 Wk4 Wk5 
Wk 
6 Wk7 Wk8 Wk9 
Wk 
12 
Off 
Study 
Informed  Consent 
x 
Concurrent  Meds 
x 
Vital Signs 
x 
Weight 
x 
EKG 
x 
x 
b 
b 
b 
b 
b 
b 
AE evaluation  (non-RSA, 
tele-  assessment)c 
x 
x 
x 
x 
CBC with diff,  pltsd 
x 
x 
%% %% %% %% %% %% %% 
Comprehensive   Panel 
x 
x 
%% %% %% %% %% %% %% 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 39 of 60 
 
 
 
 
 
Optional Rapid  COVID-19 
IgG/IgM  testing +/-  COVID- 
19 rapid antigen testing f 
x 
** 
x 
Research  blood (optional): 
SARS-CoV-2  serologyg 
x 
## 
x 
Symptom Screening 
Questionnaire  (non-RSA)h 
x 
 
aSee Section 8.0 for the timing of these tests/evaluations prior to start of therapy 
bFollowing baseline and week 1 EKG.  EKGs will be monitored weekly for the duration of the 
radiation treatment course.  Patients are eligible for more frequent EKGs if a patient is started  
on any QTc prolonging agents during therapy( Haloperidol,  ziprasidone, quetiapine, thioridazine, 
olanzapine, risperidone, amiodarone, sotalol, dofetilide, procainamide, quinidine, flecainide, 
macrolides, fluoroquinolones,  amitriptyline, imipramine, citalopram, methadone, sumatriptan, 
ondansetron, cisapride) 
cAdverse effect evaluation can be done telephonically. 
dCBC with diff, plts and Comprehensive Metabolic Panel will be allowed weekly as per standard 
of care for patients receiving concurrent chemotherapy with radiation.  For patients receiving 
radiation therapy alone, labs will be collected at the specified time points. 
eComprehensive Metabolic Panel  = albumin, alkaline phosphatase, total bilirubin, bicarbonate, 
BUN, calcium, chloride, creatinine, glucose, potassium, total protein, SGOT [AST], SGPT [ALT], 
sodium 
f   Rapid COVID-19 IgM/IgG  serology testing will be done for patients who screen as negative by 
clinical symptoms.  Patients to be managed by results per Section 9.1. 
If Rapid COVID-19 
IgM/IgG  serology is negative, when possible patients will also undergo Rapid COVID-19 Antigen 
testing.  This testing is optional but recommended. 
gResearch Blood Draw must be done via SST. 
hSee Appendix 18.2 for symptom screening questionnaire. This can be administered 
electronically, telephonically, or in person at the time of screening.  During radiation therapy, 
patients are symptom-screened for fever, cough, and COVID-19 contact prior to entering the 
building. 
**Rapid COVID-19 IgM/IgG  serology testing +/- Rapid COVID-19 antigen testing (as per Section 
9.1) will be completed for patients on treatment who develop clinical symptoms suspicious for 
COVID-19. 
## Research SARS-CoV-2 serology banking (optional but recommended): If patients presumed 
COVID-19 positive per protocol, research blood draw to occur 8-20 days after initiation of 
symptoms 
%% Periodic CBC and CMP will be obtained per standard of care for patients receiving  
concurrent chemotherapy. Dose adjustments for hydroxychloroquine  must be made based upon 
these assessments (Section 10.3). 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 40 of 60 
 
 
 
 
 
 
Note: Efforts should be made for telephone evaluations should be done when appropriate. 
 
12.1 CRITERIAFOR REMOVAL FOR STUDY 
 
Patients should permanently discontinue treatment with hydroxychloroquine or placebo in the 
event of: 
● Patients who test positive for SARS-CoV-2* will discontinue study therapy and be 
followed 
● Severe, unexpected toxicities/side effects such as (CTCAE v.5.0 grade 3 or 4) that 
cannot be managed by dose delay 
● Dose delay of greater than 14 days from the intended day of the next scheduled dose 
● Pregnancy: in the case of a patient becoming pregnant during the trial, 
hydroxychloroquine must be immediately stopped and the patient must be follow-up until 
birth or other termination of pregnancy.  Counseling on birth defect risk must be offered. 
● QTc >500 and medically unable to discontinue QTc prolonging agent 
● If the treating physician determines that it is in the best interest of the patient to stop the 
study drug. 
● Participant non-compliance with the defined by the study design 
● Participant’s right to withdraw consent for continued participation, and/or death.  In case 
a patient withdraws his/her consent for taking drug, it is of utmost importance for the 
robustness and integrity of the trial results that his/her safety data be recorded at the end 
of the 9-week period. 
 
* A patient will be declared positive for SARS-CoV-2 according to the outcomes outlined in 
section 13. 
 
Patients who discontinue from this trial are not allowed to be re-enrolled.  For patients who 
stopped the trial before enrollment, their data will be part of the description of the screening 
population, and will be replaced. 
 
13.1 CRITERIA FOR OUTCOME ASSESSMENT AND ENDPOINT EVALUABILITY 
13.2 Criteria for Therapeutic Response/Outcome Assessment 
Definitions: 
SARS-CoV-2 Positive: 
Patients who meet testing criteria will be referred for confirmatory testing and will be considered 
SARS-CoV-2 Positive if: 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 41 of 60 
 
 
 
 
● Rapid COVID-19 IgG/IgM serology testing result: positive for IgM and/or IgG (For 
symptomatic patients -his test should be administered >7 days from the onset of 
symptoms to ensure enough time has passed for antibody response) 
● MSKCC COVID-19 serology as result is positive for IgM and/or IgG (For symptomatic 
patients - this test should be administered >7 days from the onset of symptoms to 
ensure enough time has passed for antibody response) 
● Rapid COVID-19 antigen positive 
● MSKCC COVID-19 PCR positive 
● Outside laboratory COVID-19 PCR positive 
 
If patients do not screen positive for symptoms during the duration of therapy, and are COVID- 
19 IgG/IgM  serology negative at 9 weeks will be considered negative for COVID-19. 
 
Mild Symptomatic COVID-19: 
Patients who are symptomatic (Appendix 18.2) and who are considered SARS-CoV-2 positive 
but who do not meet criteria for severe COVID-19, critical COVID-19 will be considered to have 
mild symptomatic COVID-19. 
 
Severe COVID-19: 
Patients who are positive for SARS-CoV-2 (as defined above) who develop a new oxygen 
requirement attributable to COVID-19, tachypnea (RR > 20), or those who require 
hospitalization due to COVID-19 will be considered to have severe COVID-19. 
 
Critical COVID-19 / Death: 
Patients who are positive for SARS-CoV-2 (as defined above) who require care in the intensive 
care unit (ICU) or who die of COVID-19 related morbidity will be considered to belong to this 
category. 
 
Symptom and treatment toxicity will be evaluated mid-radiation treatment course, post-radiation, 
and at 9 weeks.  This will also capture high grade toxicity and hospitalization events. 
 
13.3 Criteria for Study Endpoint Evaluability 
 
Any patients who are enrolled and subsequently test positive for SARS-CoV-2 by RT-PCR 
(outside RT-PCR test results allowed) at any point during the 9 weeks following enrollment will 
be an event that is considered in the 9-week SARS-CoV-2 infection rate primary endpoint. 
 
Patients who subsequently test SARS-CoV-2 positive who require oxygenation,  hospitalization, 
or death within 12 weeks will be included in our secondary endpoint measuring SARS-CoV-2 
infection morbidity. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 42 of 60 
 
 
 
 
Withdrawal or patients who or lost to follow-up without subsequently testing SARS-CoV-2 
positive/death, or those who are removed due to toxicity will be censored. 
 
14.0 BIOSTATISTICS 
 
The primary objective of this study is to compare the rate of infection with SARS-CoV-2 at 9 
weeks from randomization in patients receiving radiotherapy or chemoradiotherapy with 
prophylactic hydroxychloroquine  versus placebo. Patients will be declared to be infected if they 
have a positive test for SARS-CoV-2 using the MSKCC or other approved assay with or without 
symptoms of infection (defined in Section 18.1). Patients who test positive using any other 
assay may be required to undergo confirmatory testing. This requirement may be waived at the 
discretion of the principal investigator. In order to ascertain the 9-week end-point, efforts will be 
made to test asymptomatic patients who did not undergo SARS-CoV-2 testing at 9 weeks after 
the start of radiation treatments. 
 
Based upon a baseline estimated SARS-CoV-2 infection rate of 40% in a New York City 
metropolitan setting in the control arm, and an estimated 20% risk of SARS-CoV-2 infection in 
the experimental arm (i.e., H0 p=40% vs. H1: p=20%), we estimate a sample size of 132  
patients will be needed with a one-sided proportion test with alpha of 0.05, power of 0.80, and 1 
early assessment when 50% of the end-points have been met. Patients will be randomized 
between the two treatment arms in a 1:1 ratio. Patients will be stratified by age (>65 vs. ≤ 65) , 
concurrent chemotherapy (yes vs. no), and weeks of radiation (>4 vs. ≤4). At the early 
assessment, when half of the endpoints have been collected, Lan-Demets spending function will 
be utilized and the trial will be stopped for futility if p-value>0.37 or efficacy if p-value<0.0055. At 
the final analysis we will reject the null hypothesis when p-value<0.048. 
 
The design of using a one-sided test with alpha=0.05 for this randomized trial has been 
extensively discussed. Due to the urgent nature of the study and the fast-changing situation of 
COVID-19, precisely estimating the enrollment rate is difficult while completing the study in a 
timely fashion is of paramount importance. We thus assume, based on clinical experience and 
knowledge of COVID-19, an enrollment rate of 50 patients per month across all MSKCC sites. 
This means that it will take approximately 3 months to randomize 132 patients. The 
implementation of a one-sided test is based on multiple existing studies showing the promising 
effect of hydroxychloroquine.  The early assessment with both futility and efficacy boundaries will 
be conducted to reduce study participants' exposure to an inferior treatment. If the accrual  
within the first 28 days is ≥100 patients, the trial will be amended to expand the accrual (at 
which time we will not have conducted the interim analysis due to the fact that the endpoint 
requires 9 weeks to collect). We will consider lowering the type 1 error rate to 0.025 with power 
still at 0.8. This will require a sample size of 166.  At the early assessment when half of the 
endpoints have been collected, the trial will be stopped for futility if p-value>0.29 or efficacy if p- 
value<0.0015. At the final analysis we will reject the null hypothesis when p-value<0.024. The 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 43 of 60 
 
 
 
 
usual intention-to-treat analysis will be applied. All patients who drop out for any reason, are lost 
to follow-up, are removed from protocol, or die of any cause without known 9-week infection 
status will be declared positive. 
 
Sample size and power calculations were completed using software R 3.6.0 and EAST 6.5. 
For secondary objectives: 
To compare the likelihood of symptomatic COVID-19 infection or death (defined in section 13.1) 
within 9 weeks from randomization, we will apply a two-sided, two-sample proportion test on 
evaluable patients for this objective. That is, for each arm, the denominator will be those 
enrolled on each arm, while the numerator is the number of such patients who have 
symptomatic COVID-19 infection within 9 weeks of randomization. 
 
To compare the likelihood of severe COVID-19 infection or death (defined in section 13.1) within 
12 weeks from randomization, we will apply a two-sided, two-sample proportion test on  
evaluable patients for this objective. That is, for each arm, the denominator will be those  
enrolled on each arm, while the numerator is the number of such patients who have severe 
COVID-19 infection requiring hospitalization or death within 12 weeks of randomization. 
 
To evaluate acute toxicity associated with administration of daily (7 days/week) 
hydroxychloroquine during radiation or chemoradiation for each arm, all acute toxicities will be 
collected and documented by grade, type and location. Once the treatment arm is unblinded, we 
will tabulate and summarize the toxicities for the hydroxychloroquine arm. For this analysis, all 
randomized subjects who received at least one dose of study drug will be included. 
 
For the correlative endpoints: 
 
Baseline prevalence of anti-SARS-CoV-2 antibodies will be summarized as sample proportion 
with confidence intervals. In patients who are serology negative, we will compare the 
symptomatic COVID-19 infection rate within 12 weeks from randomization between the two 
arms using a 2-sample, 2-sided proportion test. The rate of severe COVID-19 infection or death 
within 12 weeks from randomization will be compared similarly. Serum samples will be stored 
for future studies. 
 
15.1 TOXICITIES/SIDE EFFECTS 
 
15.2 Serious Adverse Event (SAE) Reporting 
During radiation, chemoradiation, and hydroxychloroquine administration, adverse events will be 
graded using the NCI Common Terminology Criteria for Adverse Events - Version CTCAE 
version 5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site:  
http://ctep.cancer.gov/protcolDevelopment/electronicapplications/ctc.htm. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 44 of 60 
 
 
 
 
 
 
An adverse event is considered serious if it results in ANY of the following outcomes: 
● 
Death 
● 
A life-threatening adverse event 
● 
An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization 
● 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
● 
A congenital anomaly/birth defect 
● 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or participant and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition 
 
Note: Hospital admission for a planned procedure/disease treatment is not considered an SAE. 
 
SAE reporting is required as soon as the participant starts investigational treatment/intervention. 
SAE reporting is required for 30-days after the participant’s last investigational 
treatment/intervention. Any event that occurs after the 30-day period that is unexpected and at 
least possibly related to protocol treatment must be reported. 
 
Please note: Any SAE that occurs prior to the start of investigational treatment/intervention and 
is related to a screening test or procedure (i.e., a screening biopsy) must be reported. 
 
All SAEs must be submitted in PIMS. If an SAE requires submission to the HRPP office per IRB 
SOP RR-408 ‘Reporting of Serious Adverse Events’, the SAE report must be submitted within 5 
calendar days of the event.  All other SAEs must be submitted within 30 calendar days of the 
event. 
 
The report should contain the following information: 
 
● The date the adverse event occurred 
● The adverse event 
● The grade of the event 
● Relationship of the adverse event to the treatment(s) 
● If the AE was expected 
● Detailed text that includes the following 
● An explanation of how the AE was handled 
● A description of the participant’s condition 
● Indication if the participant remains on the study 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 45 of 60 
 
 
 
 
● If an amendment will need to be made to the protocol and/or consent form and whether 
the SAE is an unanticipated problem 
15.3 External SAE Reporting 
 
No additional SAE reporting information is required by the drug supplier. 
 
15.4 Attribution of the AE: 
● Definite - The AE is clearly related to the study treatment 
● Probable - The AE is likely related to the study treatment 
● Possible - The AE may be related to the study treatment. 
● Unlikely - The AE is doubtfully related to the study treatment. 
● Unrelated - The AE is clearly not related to the study treatment. 
 
Reproductive risks: There is a risk of sterility and/or birth defects associated with this study. 
Subjects must use birth control while on this study.  Women should not breastfeed while on this 
study. 
 
15.5 Drug Interactions with Hydroxychloroquine 
● Digoxin: Concomitant hydroxychloroquine and digoxin therapy may result in increased 
serum digoxin levels: serum digoxin levels should be closely monitored in patients 
receiving combined therapy. 
● Insulin or antidiabetic drugs: Hydroxychloroquine may enhance the effects of a 
hypoglycemic treatment 
● Drugs that prolong QT interval and other arrhythmogenic drugs: Hydroxychloroquine 
prolongs the QT interval and should not be administered with other drugs that have the 
potential to induce cardiac arrhythmias. Also, there may be an increased risk of inducing 
ventricular arrhythmias if hydroxychloroquine is used concomitantly with other 
arrhythmogenic drugs. 
● Mefloquine and other drugs known to lower the convulsive threshold: 
hydroxychloroquine can lower the convulsive threshold. 
● Antiepileptics: The activity of antiepileptic drugs might be impaired if co-administered 
with hydroxychloroquine. 
● Methotrexate:  Combined use of methotrexate with hydroxychloroquine has not been 
studied and may increase the incidence of adverse effects. 
● Cyclosporin: An increased plasma cyclosporin level was reported when cyclosporin and 
hydroxychloroquine  were co-administered. 
● The following interactions have been observed on treatment with the structurally related 
substance chloroquine phosphate, and therefore cannot be ruled out for 
hydroxychloroquine. 
○ Praziquantel: Chloroquine has been reported to reduce the bioavailability of 
praziquantel. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 46 of 60 
 
 
 
 
○ Antacids and kaolin: Antacids and kaolin can reduce absorption of chloroquine; 
an interval of at least 4 hours between intake of these agents and chloroquine 
should be observed. 
○ Cimetidine: Cimetidine can inhibit the metabolism of chloroquine, increasing its 
plasma level. Concomitant use of cimetidine should be avoided. 
○ Ampicillin: In a study of healthy volunteers, chloroquine significantly reduced the 
bioavailability  of ampicillin. 
15.6 Hydroxychloroquine - Potential Adverse Events 
Uncommon  adverse events (1-10%): 
● Ocular: Risk of ocular adverse events are low in the setting of short duration of daily 
hydroxychloroquine administration.  However, rare irreversible retinal damage has been 
observed in some patients who received hydroxychloroquine sulfate. Significant risk 
factors for retinal damage include daily doses of hydroxychloroquine sulfate greater than 
6.5 mg/kg (5 mg/kg base) of actual body weight, durations of use greater than five years, 
subnormal glomerular filtration, use of some concomitant drug products such as 
tamoxifen citrate and concurrent macular disease. In a series of 1207 patients, 1 (0.08%) 
patient treated with hydroxychloroquine was found to have retinal toxicity after 7       
years of daily hydroxychloroquine at 6.98 mg/kg.46 At doses as high as 1000mg per day, 
as has been explored in cancer trials, more rapid onset retinitis has been observed.47 
 
Frequency Not Defined Adverse Events: 
● Cardiac Effects, including Cardiomyopathy and QT prolongation: 
Hydroxychloroquine  prolongs the QT interval. Ventricular arrhythmias and torsades de 
pointes have been reported in patients taking hydroxychloroquine. Postmarketing cases 
of life-threatening and fatal cardiomyopathy have been reported with use of 
hydroxychloroquine as well as with use of chloroquine. Patients may present with 
atrioventricular block, pulmonary hypertension, sick sinus syndrome or with cardiac 
complications. ECG findings may include atrioventricular, right or left bundle branch 
block.   Chronic toxicity should be considered when conduction disorders (bundle branch 
block/atrio-ventricular heart block) or biventricular hypertrophy are diagnosed. 
● Worsening of psoriasis and porphyria: Hydroxychloroquine  use in patients with 
psoriasis may precipitate a severe attack of psoriasis. When used in patients with 
porphyria the condition may be exacerbated. 
● Proximal Myopathy and Neuropathy: In patients undergoing long-term 
hydroxychloroquine therapy - skeletal muscle myopathy or neuropathy leading to 
progressive weakness and atrophy of proximal muscle groups, depressed tendon 
reflexes, and abnormal nerve conduction, have been reported. 
● Neuropsychiatric events, including suicidality: Suicidal behavior has been rarely 
reported in patients treated with hydroxychloroquine. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 47 of 60 
 
 
 
 
● Hypoglycemia: Hydroxychloroquine  has been shown to cause severe hypoglycemia 
including loss of consciousness that could be life threatening in patients treated with or 
without antidiabetic medications. 
● Hepatic/Renal Disease: Hydroxychloroquine should be used with caution in patients 
with hepatic disease or alcoholism or in conjunction with known hepatotoxic drugs. 
● Hematologic Effects/Laboratory Tests: Rarely severe blood disorders such as 
aplastic anemia, agranulocytosis, leukopenia, or thrombocytopenia, can appear. 
● Dermatologic Effects: Bleaching of hair, alopecia, pruritus, skin and mucosal 
pigmentation, photosensitivity, and skin eruptions (urticarial, morbilliform, lichenoid, 
maculopapular, purpuric, erythema annulare centrifugum, Stevens-Johnson syndrome, 
acute generalized exanthematous pustulosis, and exfoliative  dermatitis). 
 
15.6  Principles of Adverse Event Management 
 
A reduction in dosage may be necessary in patients with QTc prolonging medications, renal 
dysfunction, hepatic dysfunction, or hematologic dysfunction  due to underlying comorbidities or 
medication/chemotherapy  known to affect these organs.  General criteria for dose reduction is 
as outlined in Section 10.3. 
 
QTc Assessment and Prolongation: 
Baseline and weekly post initiation of hydroxychloroquine EKG will be completed for QTC 
monitoring for the duration of radiation therapy.  Patients with QTC >470 milliseconds at 
baseline will be excluded. Reconsideration of trial enrollment can be considered if QTC 
prolonging medications can be optimized and repeat EKG demonstrated QTC <= 470. 
 
Following initiation of hydroxychloroquine,  patients please follow the following guidelines for 
management as outlined in Section 10.3. 
 
Renal Insufficiency: 
Hydroxychloroquine is renally excreted and dose modification may be needed in the setting of 
renal insufficiency.  Prior to the start of treatment, concomitant medications must be reviewed 
for the potential risk of inducing nephrotoxicity and modified if clinically possible.  Guidelines for 
on treatment renal insufficiency are as outlined in Section 10.3. 
 
Nausea/Vomiting: Preferred antiemetic agents include non-QTC prolonging medications such 
as promethazine or lorazepam (if the patient has no allergy or contra-indication).  After a trial of 
these medications, other anti-emetics can be considered with QTC monitoring 1 week after anti- 
emetic initiation.  Principal investigators should be notified if any QTC prolonging medications 
are initiated. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 48 of 60 
 
 
 
 
Dermatitis: Grade 1 or 2 dermatitis may be managed conservatively.  Use fragrance-free 
detergents/soap and moisturiser.  Mild dermatitis may be treated with emollients and topical 
corticosteroids at the clinician’s discretion. Grade 3 or higher dermatitis should be monitored 
carefully and a dermatology consult should be obtained.  Pruritis is also a common side effect 
associated with hydroxychloroquine.   Consider antihistamine initiation, promethazine, or a 
prednisone 10 mg single daily dose. 
 
Cytopenias and myelosuppression: Patients undergoing concurrent chemotherapy as well as 
radiation therapy with radiation may experience cytopenias during the treatment course.  Refer 
to Section 10.3 for guidance and dosing adjustment considerations. 
 
Ocular: For individuals with significant risk factors (daily dose of hydroxychloroquine  sulfate 
greater than 5.0 mg/kg base of actual body weight, subnormal glomerular filtration, use of 
tamoxifen citrate or concurrent macular disease) monitoring should include referral for annual 
examinations. For individuals without significant risk factors, annual exams can be deferred in 
the setting of short-term use. 
 
Hypoglycemia: Hydroxychloroquine  may enhance efficacy of insulin and antidiabetic drugs. 
Patients presenting with clinical symptoms suggestive of hypoglycemia during treatment with 
hydroxychloroquine should have their blood glucose checked and treatment reviewed as 
necessary. A decrease in dose of insulin or antidiabetic drugs may be required. 
 
16.1 PROTECTION OF HUMAN PARTICIPANTS 
 
Participation in this trial is voluntary. All patients will be required to sign a statement of informed 
consent, which must conform to IRB guidelines. 
 
Inclusion of Women and Minorities: Patients of all races, both male and female, will be accepted 
into the protocol. ; we also take due notice of the NIH policy concerning inclusion of women and 
minorities in clinical research populations. The proposed study population is as described. 
 
Exclusion of Pregnant Women: Lactating and pregnant women are excluded because of risks 
associated with radiotherapy to the developing fetus 
Children have been excluded from this study as the study population is adults with solid tumor 
malignancy. 
Participants may not receive the study drug off protocol, with the exception of symptomatic 
patients who developed confirmed COVID-19 infection and receive hydroxychloroquine  for the 
purpose of treatment off protocol. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 49 of 60 
 
 
 
 
Benefits: It is possible that this treatment will result in reduced SARS-CoV-2 infection rates.  It is 
not known, of course, whether these or any other favorable events will occur. 
 
Costs: The patient will be responsible for the costs of standard medical care, including, CT 
scans, all drug administration fees and all hospitalizations, as well as for complications of 
treatment. Hydroxychloroquine will be supplied to patients by Rising Pharmaceuticals at no cost. 
Patients will not be responsible for the costs of blood procurement obtained for research 
purposes. 
 
Incentives: No incentives will be offered to patients/subjects for participation in the study. 
 
Alternatives: Patients may be eligible for standard of care therapy or other investigational 
studies. 
 
16.2 Privacy 
 
Every effort will be made to maintain patient confidentiality. Research and hospital records are 
confidential. Patient’s name or any other personally identifying information will not be used in 
reports or publications resulting from this study. The Food and Drug Administration or other 
authorized agencies (e.g., qualified monitors) may review patients’ records and pathology 
slides, as required. 
16.3 Data Management 
 
A Clinical Research Coordinator (CRC) will be assigned to the study. The responsibilities of the 
CRC include project compliance, data collection, abstraction and entry, data reporting, 
regulatory monitoring, problem resolution and prioritization, and coordinate the activities of the 
protocol study team. 
 
The data collected for this study will be entered into a secured database at Memorial Sloan- 
Kettering Cancer Center. Source documentation will be available to support the computerized 
patient record. Data will be stored in Medidata. 
16.4 Quality Assurance 
 
Routine data quality reports will be generated to assess missing data and inconsistencies. 
Accrual rates and extent and accuracy of evaluations and follow-up will be monitored 
periodically throughout the study period and potential problems will be brought to the attention 
of the study team for discussion and action. Random-sample data quality and protocol 
compliance audits may be conducted by the study team, at a minimum of two times per year, or 
more frequently if indicated. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 50 of 60 
 
 
 
 
16.5 Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan Kettering were approved by 
the National Cancer Institute in August 2018. The plans address the new policies set forth by 
the NCI in the document entitled “Policy of the National Cancer Institute for Data and Safety  
Monitoring  of Clinical Trials.” 
 
There are several different mechanisms by which clinical studies are monitored for data, safety 
and quality. At a departmental/PI level there exists procedures for quality control by the 
research team(s). Institutional processes in place for quality assurance include protocol 
monitoring, compliance and data verification audits, staff education on clinical research QA and 
two institutional committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Deputy Physician-In-Chief,  Clinical Research. 
During the protocol development and review process, each protocol will be assessed for its level 
of risk and degree of monitoring required. 
The MSK DSMB monitors phase III trials and the DSMC monitors non-phase III trials.  The 
DSMB/C have oversight over the following trials: 
● 
MSK Investigator Initiated Trials (IITs; MSK as sponsor) 
● 
External studies where MSK is the data coordinating center 
● 
Low risk studies identified as requiring DSMB/C review 
The DSMC will initiate review following the enrollment of the first participant/or by the end of the 
year one if no accruals and will continue for the study lifecycle until there are no participants 
under active therapy and the protocol has closed to accrual. The DSMB will initiate review once 
the protocol is open to accrual. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 51 of 60 
 
 
 
 
17.0  REFERENCES 
 
1. Simpson S, Kay FU, Abbara S, et al: Radiological Society of North America Expert 
Consensus Statement on Reporting Chest CT Findings Related to COVID-19. Endorsed by the 
Society of Thoracic Radiology, the American College of Radiology, and RSNA. Radiology: 
Cardiothoracic Imaging 2:e200152, 2020 
2. Shi Y, Yu X, Zhao H, et al: Host susceptibility to severe COVID-19 and establishment of a 
 
host risk score: findings of 487 cases outside Wuhan. Crit Care 24:108, 2020 
 
3. Yang J, Zheng Y, Gou X, et al: Prevalence of comorbidities in the novel Wuhan coronavirus 
(COVID-19) infection: a systematic review and meta-analysis. Int J Infect Dis , 2020 
4. Liang W, Guan W, Chen R, et al: Cancer patients in SARS-CoV-2 infection: a nationwide 
 
analysis in China. Lancet Oncol 21:335–337, 2020 
 
5. Guzzinati S, Virdone S, De Angelis R, et al: Characteristics of people living in Italy after a 
cancer diagnosis in 2010 and projections to 2020. BMC Cancer 18:169, 2018 
6. Onder G, Rezza G, Brusaferro S: Case-Fatality Rate and Characteristics of Patients Dying in 
Relation to COVID-19 in Italy. JAMA , 2020 
7. Devaux CA, Rolain J-M, Colson P, et al: New insights on the antiviral effects of chloroquine 
 
against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents 105938, 2020 
 
8. Keyaerts E, Li S, Vijgen L, et al: Antiviral activity of chloroquine against human coronavirus 
OC43 infection in newborn mice. Antimicrob Agents Chemother 53:3416–3421, 2009 
9. Wang M, Cao R, Zhang L, et al: Remdesivir and chloroquine effectively inhibit the recently 
 
emerged novel coronavirus (2019-nCoV) in vitro. Cell Research 30:269–271, 2020 
 
10. Olofsson S, Kumlin U, Dimock K, et al: Avian influenza and sialic acid receptors: more than 
meets the eye? Lancet Infect Dis 5:184–188, 2005 
11. Liu J, Cao R, Xu M, et al: Hydroxychloroquine, a less toxic derivative of chloroquine, is 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 52 of 60 
 
 
 
 
 
effective in inhibiting SARS-CoV-2 infection in vitro. Cell Discovery 6:1–4, 2020 
 
12. Gao J, Tian Z, Yang X: Breakthrough: Chloroquine phosphate has shown apparent efficacy 
in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends 14:72–73, 
2020 
13. multicenter collaboration group of Department of Science and Technology of Guangdong 
Province and Health Commission of Guangdong Province for chloroquine in the treatment of 
novel coronavirus pneumonia: Expert consensus on chloroquine phosphate for the treatment of 
novel coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi 43:185–188, 2020 
14. Gautret P, Lagier J-C, Parola P, et al: Hydroxychloroquine and azithromycin as a treatment 
of COVID-19: results of an open-label non-randomized clinical trial. International Journal of 
Antimicrobial Agents 105949, 2020 
15. Cortegiani A, Ingoglia G, Ippolito M, et al: A systematic review on the efficacy and safety of 
chloroquine for the treatment of COVID-19. J Crit Care , 2020 
16. Chen J, Liu D, Liu L, et al: A pilot study of hydroxychloroquine in treatment of patients with 
 
common coronavirus disease-19 (COVID-19). J Zhejiang  Univ 49:0–0, 2020 
 
17. Yu J, Ouyang W, Chua MLK, et al: SARS-CoV-2 Transmission in Patients With Cancer at a 
Tertiary Care Hospital in Wuhan, China [Internet]. JAMA  Oncol , 2020[cited 2020 Mar 26] 
Available   from: https://jamanetwork.com/journals/jamaoncology/fullarticle/2763673 
18. Schwartz E: Prophylaxis of malaria. Mediterr J Hematol Infect Dis 4:e2012045, 2012 
 
19. Lauer SA, Grantz KH, Bi Q, et al: The Incubation Period of Coronavirus Disease 2019 
(COVID-19) From Publicly Reported Confirmed Cases: Estimation and Application [Internet]. 
Ann Intern Med , 2020[cited 2020 Mar 26] Available from: 
https://annals.org/aim/fullarticle/2762808/incubation-period-coronavirus-disease-2019-covid-19- 
from-publicly-reported 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 53 of 60 
 
 
 
 
20. Rosenfeld MR, Ye X, Supko JG, et al: A phase I/II trial of hydroxychloroquine in conjunction 
with radiation therapy and concurrent and adjuvant temozolomide in patients with newly 
diagnosed glioblastoma multiforme. Autophagy 10:1359–1368, 2014 
21. Eldredge HB, Denittis A, Duhadaway JB, et al: Concurrent Whole Brain Radiotherapy and 
Short-Course Chloroquine in Patients with Brain Metastases: A Pilot Trial. J Radiat Oncol 2, 
2013 
22. Hong TS, Wo JY-L, Jiang W, et al: Phase II study of autophagy inhibition with 
 
hydroxychloroquine (HCQ) and preoperative (preop) short course chemoradiation (SCRT) 
followed by early surgery for resectable ductal adenocarcinoma of the head of pancreas 
(PDAC). JCO 35:4118–4118, 2017 
23. Rangwala R, Leone R, Chang YC, et al: Phase I trial of hydroxychloroquine with dose- 
 
intense temozolomide in patients with advanced solid tumors and melanoma. Autophagy 
10:1369–1379,  2014 
24. Goldberg SB, Supko JG, Neal JW, et al: A phase I study of erlotinib and hydroxychloroquine 
 
in advanced non-small-cell lung cancer. J Thorac Oncol 7:1602–1608, 2012 
 
25. Boone BA, Bahary N, Zureikat AH, et al: Safety and Biologic Response of Pre-operative 
Autophagy Inhibition  in Combination with Gemcitabine in Patients with Pancreatic 
Adenocarcinoma. Ann Surg Oncol 22:4402–4410, 2015 
26. Zeh H, Bahary N, Boone BA, et al: A Randomized Phase II Preoperative Study of 
Autophagy Inhibition  With High-Dose Hydroxychloroquine  and Gemcitabine/Nab-Paclitaxel in 
Pancreatic Cancer Patients. Clin Cancer Res , 2020 
27. Karasic TB, O’Hara MH, Loaiza-Bonilla A, et al: Effect of Gemcitabine and nab-Paclitaxel 
With or Without Hydroxychloroquine  on Patients With Advanced Pancreatic Cancer: A Phase 2 
Randomized Clinical Trial. JAMA Oncol 5:993–998, 2019 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 54 of 60 
 
 
 
 
28. Project TCT: The COVID Tracking Project [Internet]. The COVID Tracking Project [cited 
2020 Mar 26] Available from: https://covidtracking.com 
29. Wu Z, McGoogan JM: Characteristics of and Important Lessons From the Coronavirus 
 
Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the 
Chinese Center for Disease Control and Prevention. JAMA , 2020 
30. Ferguson NM, Laydon D, Nedjati-Gilani  G, et al: Impact of non-pharmaceutical interventions 
(NPIs) to reduce COVID- 19 mortality and healthcare demand20, 2020 
31. The Lancet  null: COVID-19: protecting health-care workers. Lancet 395:922, 2020 
 
32. Wang C, Liu L, Hao X, et al: Evolving Epidemiology and Impact of Non-pharmaceutical 
Interventions on the Outbreak of Coronavirus Disease 2019 in Wuhan, China. medRxiv 
2020.03.03.20030593,  2020 
33. Li R, Pei S, Chen B, et al: Substantial undocumented infection facilitates the rapid 
dissemination of novel coronavirus (SARS-CoV2). Science eabb3221, 2020 
34. McMichael TM: COVID-19 in a Long-Term Care Facility — King County, Washington, 
 
February 27–March 9, 2020 [Internet]. MMWR Morb Mortal Wkly Rep 69, 2020[cited 2020 Mar 
26] Available  from: https://www.cdc.gov/mmwr/volumes/69/wr/mm6912e1.htm 
35. Up to 70% of Germany could contract virus - Merkel [Internet]. BBC News , 2020[cited 2020 
Mar 26] Available  from: https://www.bbc.com/news/world-us-canada-51835856 
36. White JB: Newsom: More than half of California could contract coronavirus with no 
mitigation [Internet]. Politico PRO [cited 2020 Mar 26] Available  from: https://politi.co/2xTJn3K 
37. Pfefferle S, Reucher S, Nörz D, et al: Evaluation of a quantitative RT-PCR assay for the 
 
detection of the emerging coronavirus SARS-CoV-2 using a high throughput system. Euro 
Surveill 25, 2020 
38. Lan L, Xu D, Ye G, et al: Positive RT-PCR Test Results in Patients Recovered From 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 55 of 60 
 
 
 
 
 
COVID-19. JAMA , 2020 
 
39. Li Z, Yi Y, Luo X, et al: Development and Clinical Application of A Rapid IgM-IgG  Combined 
Antibody Test for SARS-CoV-2 Infection Diagnosis. J Med Virol , 2020 
40. Zhao J, Yuan Q, Wang H, et al: Antibody responses to SARS-CoV-2 in patients of novel 
coronavirus disease 2019 [Internet]. Infectious Diseases (except HIV/AIDS),  2020[cited 2020 
Mar 26] Available  from: http://medrxiv.org/lookup/doi/10.1101/2020.03.02.20030189 
41. Chung M, Bernheim A, Mei X, et al: CT Imaging Features of 2019 Novel Coronavirus (2019- 
 
nCoV). Radiology 295:202–207, 2020 
 
42. Bernheim A, Mei X, Huang M, et al: Chest CT Findings in Coronavirus Disease-19 (COVID- 
19): Relationship to Duration of Infection. Radiology 200463, 2020 
43. Wang Y, Dong C, Hu Y, et al: Temporal Changes of CT Findings in 90 Patients with COVID- 
 
19 Pneumonia: A Longitudinal Study. Radiology 200843, 2020 
 
44. Ai T, Yang Z, Hou H, et al: Correlation of Chest CT and RT-PCR Testing in Coronavirus 
Disease 2019 (COVID-19) in China: A Report of 1014 Cases. Radiology 200642, 2020 
45. Fang Y, Zhang H, Xie J, et al: Sensitivity of Chest CT for COVID-19: Comparison to RT- 
PCR. Radiology 200432, 2020 
46. Levy GD, Munz SJ, Paschal J, et al: Incidence of hydroxychloroquine retinopathy in 1,207 
 
patients in a large multicenter outpatient practice. Arthritis & Rheumatism 40:1482–1486, 1997 
 
47. Leung L-SB, Neal JW, Wakelee HA, et al: Rapid Onset of Retinal Toxicity From High-Dose 
Hydroxychloroquine  Given for Cancer Therapy. Am J Ophthalmol 160:799-805.e1, 2015 
 
18.1 APPENDICES 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 56 of 60 
 
 
 
 
18.2 COVID19 Symptom Questionnaire for patients and Testing Algorithm for Providers 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 57 of 60 
 
 
 
 
 
 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 58 of 60 
 
 
 
 
18.2. MSKCC Radiation Oncology Department Guidelines for Radiation Therapyin 
COVID19-positive or COVID19 suspected patients (as of 3/24/2). 
 
● COVID positive patients: 
○ Outpatients - will take direction of the Department of Health about Quarantine 
and follow Workflow A below. 
○ Inpatients - DEcision for treatment to be made based on Workflow B below. 
● Patients at risk for COVID who are symptomatic:   This category includes patients 
who are symptomatic (Temp >38C in addition to sore throat, cough, shortness of breath, 
wheezing, chest tightness, body aches or chills, diarrhea, anosmia), regardless of risk of 
exposure 
○ Non-urgent radiation treatment (can hold treatment for 2-4 days): Mandate 
test before treatment, and hold treatment until treatment results.  We anticipate 
that at the current testing capability, which is continuously increasing, this 
timeframe should only be 1-4 days. 
○ Urgent radiation treatment (e.g. cannot hold treatment for 2-4 days): Treat 
based on clinical judgement (of the treating radiation oncologist) as above (as if 
positive). 
● Patients who are at high risk for COVID due to exposure but who are symptomatic 
(including those in self-quarantine) 
○ Current MSKCC policy as of 3/24/20 has not made SARS-CoV-2 testing 
available yet for these patients.  If a patient notifies the clinic/attending that they 
had an exposure and are not symptomatic: 
■ Non-urgent per treating attending (can hold treatment for 2-4 days). 
Please hold treatment until 5 days after reported exposure.  If the patient 
develops symptoms during this time, follow policy in #2 above.  If 
asymptomatic 5 days after exposure, resume treatment with a mask until 
day 14 after exposure. 
■ Urgent per treating attending (e.g. cannot hold treatment for 2-4 days). 
Attending of record to discuss with service chief, disease site director, 
and departmental leadership per steps 2-7 in Workflow A below.  If 
treated without break, the patient will be added to the schedule at the end 
of the day with appropriate protective measure taken. 
● Workflow A:  COVID19-positive outpatients: 
○ When a staff member is informed that a patient is COVID19 positive, e-mail the 
a) service chief, b) attending of record and c) radiation therapy chiefs, at 
zzPDL_RAO-chief_RTTs. 
○ The attending of record and service chief will arrange to contact the patient and 
inform them to not come into the department until a decision is made about 
continuing treatment, over the next business day. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 59 of 60 
 
 
 
 
○ Treating physician to discuss case with disease site director, including urgency of 
treatment and clinical implications of holding until COVID19 negative. 
○ Case to be reviewed on COVID19 daily huddle call in afternoon (typically 3:30), 
to determine whether the patient should continue treatment or be given a 
treatment break.  This wall will include: a) the disease site director of the case in 
question, b) operational leadership team (Dr. Powel, Dr. Cahlon, service chiefs), 
and c) managers from therapy, nursing, and our APP team.  The primary 
attending will also be invited to the huddle to discuss the case and can opt to 
participate if they would like. 
○ Decision regarding treatment will be communicated to the patient and other 
treating physicians by the primary attending and schedule adjusted accordingly. 
The primary attending and disease site director will be responsible for 
determining a fractionation scheme to account for treatment breaks and to 
minimize the negative impact on outcome. 
○ Patients who receive radiation will be treated at the end of the day with 
appropriate cleaning and precautions. 
○ Over time, and depending on the number of COVID19+ patients, we hope to 
develop an algorithm with each disease site so that each case will not require a 
full discussion. 
● Workflow B: COVID19-positive inpatients at Memorial Hospital; 
○ When a staff member is informed that a patient is COVID19 positive, e-mail the: 
a) service chief, b) attending of record and c) radiation therapy chiefs, at 
zzPDL_RAO_chief_RTTs 
○ If a decision regarding treatment can be deferred until the daily departmental 
huddle, follow the workflow above. 
○ If the clinical situation is emergent, the primary physician should speak with the 
disease site director, service chief, and department leadership for a prompt 
decision. 
○ If the consensus is that emergent treatment is needed, the service chief and 
attending of record will arrange for the patient to be treated at the end of the day, 
with appropriate cleaning and precautions. 


Memorial Sloan Kettering Cancer Center 
IRB Number: 20-176 A(1) 
Approval date: 07-May-2020 
Memorial  Sloan Kettering Cancer Center 
1275 York Avenue 
New York, New York 10065 
Page 60 of 60 
 
 
 
 
18.3 QT Prolonging agents 
Haloperidol, ziprasidone, quetiapine, thioridazine,  olanzapine, risperidone, amiodarone,  
sotalol, dofetilide, procainamide, quinidine, flecainide, macrolides, fluoroquinolones,  
amitriptyline, imipramine, citalopram, methadone, sumatriptan, ondansetron, cisapride.  Please 
check uptodate with the addition of any new medications to determine whether it is a QTc 
prolonging agent. 
 
18.4 Management Algorithm for Positive Screen 
- 
The study PI or CoPIs must be notified by email or phone 
- 
Patients who have a positive symptom screen will undergo testing per MSKCC 
COVID19 testing protocol. 
- 
If patient is SARS-CoV2 positive by SARS-CoV-2 PCR at MSKCC or any outside 
laboratory facilities 
- 
Subsequent prescriptions of study drug will be canceled 
- 
The patient should be instructed to discontinue study and undergo 
management per MSKCC Infectious Diseases Guidelines in conjunction 
with the treating team. 
- 
Patient’s remaining radiation treatment course will be completed per 
MSKCC Radiation Oncology Department guidelines for COVID19 positive 
patients 
- 
If patients is SARS-CoV2 negative, patient will continue on the protocol 
- 
Patients who have had no change in symptom screen symptoms with interval negative 
test will not be retested