Clinical trial: NCT02535247
Section: Alternatives
Subsections: What Other Choices Do You Have If You Do Not Take Part In This Research Study?

Your other choices may include:
Getting treatment or care for your cancer without being in a study Taking part in another study Getting no treatment Getting comfort care, also called palliative care. This type of care helps reduce pain, tiredness, appetite problems and other problems caused by the cancer. It does not treat the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible
Talk to your doctor about your choices before you decide if you will take part in this study.
Clinical trial: NCT02535247
Section: Confidentiality
Subsections: Will Your Medical Information Be Kept Private?

We will do our best to make sure that the personal information in your medical record will be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used.  
Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include:
Fox Chase Cancer Center and affiliated Joint Centers, The Institutional Review Boards of The Fox Chase Cancer Center and Temple University, Temple University, Temple University Health system, Inc., and its affiliates or subsidiaries and other authorized representatives of these organizations.  
Merck Sharp & Dohme Corp., (a subsidiary of Merck & Co. Inc.) Bayer The National Cancer Institute (NCI) and other government agencies, like the Food and Drug Administration (FDA), involved in keeping research safe for people Study team members at collaborating sites
A description of this clinical trial will be available on *http://www.ClinicalTrials.gov*, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.  
You will be given a separate form to review regarding the steps we will take to guard your privacy as part of your participation in the research study. By signing that additional authorization, you will be providing your consent to use and disclose information described in that form connected with your participation in this research study.
Clinical trial: NCT02535247
Section: Participant's Rights
Subsections: What Are Your Rights If You Take Part In This Research Study?

Taking part in this research study is your choice. You may choose either to take part or not to take part in the research study. If you decide to take part in this study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our institution. In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this form.
Clinical trial: NCT02535247
Section: Possible Risks, Discomforts, and Inconveniences
Subsections: What Side Effects Or Risks Can You Expect From Being In The Research Study?|Common (1% To 10%) Uncommon (0.1 To < 1%)|Rare (0.01% To 0.1%)|Other Events That May Occur But Can Not Be Estimated From The Available Data Solid Organ Transplant Rejection|Very Common (≥ 10%)|Common (≥ 1% To < 10 %):|Opportunistic Infections:|Are There Benefits To Taking Part In The Study?|What If You Are Injured While Taking Part In This Research Study?

You may have side effects while on the research study. Everyone taking part in the research study will be watched carefully for any side effects. However, doctors don't know all the side effects that may happen. Side effects may be mild or very serious. Your health care team may give you medicines to help lessen side effects. Many side effects go away soon after you stop taking the pembrolizumab and/or copanlisib. In some cases, side effects can be serious, long lasting, or may never go away. You should talk to your study doctor about any side effects that you have while taking part in the research study. Risks and side effects related to the **Pembrolizumab** include those which are:  
Very Common (≥ **10%)**
Fatigue - feeling tired Decreased hunger Cough Pruritus- itching of the skin Diarrhea- loose or watery stool Rash Nausea Shortness of breath Joint pain Constipation Headache Vomiting Asthenia- abnormal physical weakness or lack of energy Fever Back pain Anemia- lack of red blood cells resulting in pale color and weakness Peripheral edema- swelling or puffiness in the body due to too much liquid accumulation in body's tissues, especially, lower limbs Pneumonia- infection of the lungs in which your lungs get filled with fluid leading to shortness of breath and cough with phlegm or pus, fever, chills. Sometimes this might lead to death Hyperthyroidism- too much thyroid hormone so you may feel anxious, angry, can't sleep, weak, tremble, increased sweating, weight loss, hair loss, tired, have diarrhea Hypothyroidism- not enough thyroid hormone so you may feel tired, gain wright, feel cold, have infrequent or hard stools Pleural effusion- water in the lungs that may lead to cough, sharp chest pain, or shortness of breath Pneumonitis- inflammation of lungs, symptoms may include shortness of breath, cough, fatigue, loss of appetite and unintentional weight loss Colitis- chronic digestive disease of inflammation of the bowels/ gut, which may cause severe pain in your belly with loose or water stools, and black, tarry, sticky stools or stools with blood or mucus, loss of appetite Pulmonary embolism- sudden chest pain and shortness of breath

Infusion related reaction (drug hypersensitivity, anaphylactic reaction, hypersensitivity and cytokine release syndrome)- allergic reaction to infusion where you may feel dizzy or faint, flushed, get a rash, have a fever, feel short of breath at the time of receiving your infusion
(IV) or just after, or pain at the site of infusion of the drug Change in taste Dehydration Pain in your belly Acute kidney injury- sudden kidney failure Skin cancer Chronic obstructive pulmonary disease (COPD)- symptoms may include shortness of breath, wheezing, or a chronic cough Pericardial effusion- accumulation of water around heart Cellulitis- a painful bacterial skin infection Kidney failure Urinary tract infection- it may cause pelvic pain, increased urge to urinate, pain with urination, and blood in the urine Respiratory failure

Thyroiditis- inflammation of the thyroid gland, an organ that makes and stores thyroid hormones. This condition may lead to change in your heart rate, body temperature, and the rate at which food is converted into energy, sensitivity to cold, puffy face, dry hair, dry skin, weight gain or loss, fatigue, diarrhea or constipation Severe skin reactions- inflammation of the skin so you may have peeling of the skin, itchiness, and/ or skin redness. The skin inflammation (i.e. peeling, itching and redness) could also be widespread throughout your body. More severe skin reactions may involve the inside of your mouth, the surface of your eye and genital areas, and/ or may cause the top layer of your skin to peel from all over your body which can cause severe infection. These severe conditions can sometimes lead to death Sepsis- this is caused by body's over-reaction to infection, symptoms may include fever, difficulty in breathing, low blood pressure, fast heart rate and mental confusion Irregular heartbeat Hypophysitis- inflammation of the pituitary gland (a gland in the head), which may cause you to feel sick to your stomach or have headaches, changes in your behavior, double vision, few to no menstrual cycles, weakness, vomiting and dizziness or fainting, extreme thirst Adrenal insufficiency- Adrenal glands (glands on top of the kidneys) that may not make enough hormone, which could cause tiredness, weight loss, muscle weakness, feeling faint, joint, muscle and belly aches, nausea, vomiting, loose or watery tools, fever, salt craving, and sometimes darkening of the skin like a suntan Type 1 diabetes mellitus (diabetic ketoacidosis)- type 1 diabetes, a condition that can cause too much sugar in your blood, feeling thirstier than usual, frequent urination and weight loss. You are likely to need regular insulin shots, a diabetic complication where body produces too much acid Hyponatremia- low level of sodium in the body, symptoms may include nausea, headache, confusion and fatigue, restlessness and irritability, muscle weakness or spasms, seizure, coma Uveitis (iritis, iridocyclitis)- inflammation of the eye so you may have blurred vision, sensitivity to light, eye pain, see floaters or have headaches Myositis- inflammation of the muscles so you may feel weak or have pain in your muscles Myocarditis- inflammation of the middle layer of your heart wall that may cause your heart to have difficulty pumping blood throughout your body, which can cause chest pain, shortness of breath and swelling of the legs. You may experience a fast or irregular heartbeat that may cause dizziness or fainting. Sometimes this condition can lead to death Pancreatitis- inflammation of the pancreas (a gland in your abdomen that controls sugar level) so you may have severe pain in the top part of your belly that may move to your back, feel sick to your stomach, and vomiting that gets worse when you eat Hepatitis- inflammation of the liver that may make you feel sick to the stomach and vomit, feel like not eating, feel tired, have a mild fever, have pain in the right side of the belly, yellow eyes and skin, and dark urine Nephritis- inflammation of the kidney so you may pass less urine or have cloudy or bloody urine, swelling in the face, legs and feet, and lower back pain  
Guillain-Barre Syndrome- an autoimmune condition where your immune system attacks your nerves that may cause severe lower back pain, muscle weakness in your legs that travels to your upper body, prickling or tingling sensation in your fingers and toes, paralysis, loss of bladder control, difficulty moving your eyes or face, talking, chewing or swallowing, fast heart rate, difficulty breathing Myasthenic syndrome- a condition that may make you feel weak and tired and might have drooping of the eyelids, blurred or double vision, difficulty swallowing, slurred speech, weakness in your arms and legs, or difficulty breathing Sarcoidosis- the formation of small clusters of immune cells (called granulomas) in parts of your body, such as, your lymph nodes, eyes, skin or lungs, symptoms vary depending on the organ affected and includes shortness of breath, cough that won't go away, reddish bumps on the skin, fever, fatigue, night sweats, weight loss Encephalitis- inflammation of the brain with confusion and fever. This may also include:
disorientation, memory problems, seizures (fits), changes in personality and behavior, difficulty speaking, weakness or loss of movement in some parts of your body, and loss of consciousness Toxic epidermal necrolysis- a disorder of skin and outer lining that may cause a painful, red are that spreads quickly, skin may peel without blistering, raw areas of skin, discomfort, condition may spread to eyes, mouth/throat, and genitals/ urethra/ anus Stevens-Johnson syndrome- a disorder of the skin and outer lining that may begin with flu like symptoms, a painful rash that spreads and blisters follow, peeling of the skin, rash of small purplish spots, red spots or bumps, fever, malaise, eye redness, coughing, itching, mouth ulcers, sensitivity to light, sore throat or swelling

Patients treated with pembrolizumab who then go on to allogeneic stem cell transplant (a procedure in which a person receives blood-forming stem cells from a donor), should inform their transplant physician that they may have received pembrolizumab in the past.  
In patients with any hematologic malignancy (cancers of the blood, like, Hodgkin lymphoma, multiple myeloma): there is a potential for an increased risk of severe complications following allogeneic stem cell transplant in patients who previously received pembrolizumab.  
Reports of clotting of blood within the liver and severe graft versus host disease (which may include skin, liver and gastrointestinal symptoms), including death, have been received for patients who received allogeneic stem cell transplant after pembrolizumab therapy. Risks and side effects related to the **Copanlisib** include those which are:

Decrease in white blood cells (leukopenia) which can interfere with the ability to fight infections Decreased hemoglobin [anemia, hemoglobin decreased] leading to tiredness and pale skin, and may become life-threatening Raised blood sugar levels [hyperglycemia]. In some instances this may be severe and lifethreatening
Raised blood pressure [hypertension including hypertensive emergency]
Feeling tired [fatigue and asthenia] Nausea Diarrhea Inflammation of the mouth and lips (stomatitis) with or without oral ulceration and oral pain Rash Low phosphate levels in the blood (hypophosphatemia) that can cause muscle weakness, respiratory failure and heart failure, seizures and coma Decreased number of a type of white blood cells called neutrophils [neutropenia]. This may occur with other signs of infection and may become life-threatening [neutropenia]
Decreased number of a component of blood called platelets that help with the formation of blood clots [thrombocytopenia, platelet count decreased].  
Lower respiratory tract infections (including pneumonia, pneumonia due to bacteria, virus or a fungal infection). Such infections may be severe and have life threatening or fatal outcome.

Low levels of a type of blood cells called lymphocytes (lymphopenia) causing weakness, tired, weight loss, chills, fever, night sweats, pain or feeling of fullness in the belly Change in your sense of taste (dysgeusia) High level of disease-fighting white blood cells known as eosinophils in the blood
(eosinophilia) that can cause allergies, asthma, inflammatory conditions in the stomach and skin, such as, eczema Febrile neutropenia- development of fever with infection due to low number of a cell type in the blood (neutrophils) that can be life threatening Dry mouth Difficulty swallowing (Dysphagia) Swelling in the lining of intestines (mucosal inflammation)
Injection site reactions Hypersensitivity reactions (including allergic swelling of the skin (edema and angioedema), widening of blood vessels and flushing, and infusion related reaction)
High levels of enzymes lipase and amylase that can cause severe abdominal pain, fever, loss of appetite, nausea, vomiting, yellowing of eyes High lipids, such as cholesterol and triglycerides (hyperlipidemia)
High levels of insulin in the blood (hyperinsulinaemia) causing weight gain, craving or sugar, intense hunger at higher frequency, feeling anxious, fatigue and lacking focus Abnormal feeling of constant thirst (polydipsia paresthesia)
Unpleasant, abnormal sense of touch often present as pain or an inappropriate but not discomforting sensation (dysesthesia)
Pneumonitis (including interstitial lung disease and noninfectious pneumonitis)
Sudden hair loss that starts with one or more circular bald patched (alopecia)

During treatment with copanlisib you may develop bacterial or viral infection. In order to prevent developing of such infections additional tests will be performed on a regular basis. Your physician may advise using prophylactic treatment for this kind of infection at any time during treatment with copanlisib.  
As the study drug is under development, there may be side effects, including allergies that are not yet known. Therefore, you must notify your study doctor of any new symptoms that you may have whether or not you think they are caused by the study drug.  
You may experience some of these side effects, which are usually temporary and manageable. However, this study may include risks that are yet unknown and may cause serious problems or even death.  
Radiation Risk for Diagnostic Imaging It is unlikely that there will be any harmful effects from the radiation exposure you will receive from participating in this study At high levels of exposure, scientists agree that radiation can cause cancer At low exposure levels most scientists agree that the risk, if any, is very low. You will have low levels of radiation exposure with diagnostic imaging procedures Risks from exposure to radiation may accumulate over a lifetime CT Scan: CT scans are used to create images of internal bones and organs using radiation o High dose radiation is known to produce cancer cells. The effect of exposure to radiation adds up over a lifetime o The amount of radiation exposure involved in this trial will not be significantly greater than for subjects with your disease who do not take part in the trial.  
o The contrast solution that may be given for a CT scan may cause an allergic reaction (rare)
Severe allergic reactions can be life threatening CT contrast solution can cause kidney damage, especially if you are diabetic, dehydrated (lost body water) or elderly Blood Draw Risks Fainting Lightheadedness Bleeding at the place on your arm where the blood was drawn or needle inserted Bruising at the place on your arm where the blood was drawn or needle inserted Pain at the place on your arm where the blood was drawn or needle inserted Swelling Infection (rare)
IV line Risks Discomfort Irritation Mild bruising Bleeding Leakage of drug solution, and rarely, infection, nausea, and lightheadedness.  
Biopsy Risks Bleeding Pain Infection, which can be life-threatening or fatal in rare cases
Other less common side effects have been reported with the use of the drugs in this study. The study doctor or staff can discuss these with you. There may also be other side effects or risks that are not known at this time.  
Reproductive Risks Study treatments may make you sterile (unable to have children) The drugs in this study may affect a baby, before or after the baby is born If you are pregnant now or if you are breast-feeding now, you may not take part in this research study If you become pregnant while you are on the research study, you must notify the study doctor right away. The study drug will be stopped and you may not continue to take part in the research study For women who can become pregnant: You should not become pregnant while you are in this study and up to 120 days after the last dose of study therapy You should not breast-feed your baby while taking drugs for this research study The study doctor will perform blood pregnancy tests before the start of and during the study, if you are able to have a baby

Taking part in this study may or may not make your health better. While doctors hope the treatment will be more useful against cancer compared to the usual treatment, there is no proof of this yet. We do know that the information from this study will help doctors learn more about pembrolizumab and copanlisib as a treatment for cancer. This information could help future cancer patients. The sponsor does not intend to provide you with ownership or financial benefits that may result from this study.

If you are injured as a result of your participation in this research study, seek immediate medical care. Temple University Health System or its subsidiaries will treat the injury, though there is no commitment to provide monetary compensation or free medical care. Other financial compensation (such as lost wages or pain and suffering) for such injuries is not available.
Clinical trial: NCT02535247
Section: Procedures
Subsections: What Will Happen If You Take Part In This Research Study? Before You Begin The Research Study:|During The Research Study Study Treatment|Tests And Procedures|After You Are Finished With The Study Treatment

You will need to have the following exams, tests or procedures to find out if you can be in the research study. These exams, tests or procedures are part of regular cancer care and may be done even if you do not join the research study. If you have had some of them recently, they may not need to be repeated. This will be up to your study doctor.  
Physical exam which will include height, weight and vital signs You will be asked questions about your medical history and daily activities You will be asked about the medicines you are taking or have recently taken (over-thecounter medications, supplements, prescription medications or illegal drugs)
You will be asked about any side-effects you may be experiencing You will be asked to provide a tumor sample from a previous biopsy or surgical procedure if available. You will also be asked to provide a newly obtained tumor biopsy tissue sample o This sample will be tested to ensure it can be evaluated for the specific biomarkers to be tested in this study. Your sample may also be used for the analysis of additional biomarkers to investigate ways that the study drug does or does not work to shrink tumors o Other additional biomarkers which may impact how individuals respond to the study drug may also be analyzed o Any sample left over after these tests will be stored for future research if you consent to the optional Future Biomedical Research (FBR) sub-study Routine blood tests (about 1 tablespoon)
o These samples will be used to check blood counts, kidney and liver function, thyroid function and the levels of certain enzymes and minerals normally found in the blood Blood (1 teaspoon) to test how fast your blood takes to clot A PET/CT scan or CT scan of your tumor o A PET scan requires an injection of a radioactive material into a vein and produces 3-D images to see how your cells work.  
o A CT scan is a computerized x-ray that gives your study doctor pictures of the inside of your body o A PET/CT scan combines the two scans to allow doctors to see the location and function of cells within the body Urine test Blood pregnancy test (1 teaspoon), if you are a female and able to become pregnant We will perform a blood test to check the presence of a viral infection (CMV)

This study has two cohorts, cohort 1 and cohort 2. Patients in cohort 1 will be treated with pembrolizumab alone while patients in cohort 2 will be treated with the combination of pembrolizumab and copanlisib. Cohort 1 is already completed and therefore you will be enrolled in cohort 2. Cohort 2: This cohort has two phases of treatment, phase 1 and phase 2. In this cohort you will be asked to take Bactrim drug either one tablet daily (single strength) or three times a week (double strength) to prevent infections. This cohort has an induction phase prior to treatment cycles where patients will be infused with one of the drugs, copanlisib, twice- on day -21 and day
-14 of 21 day period (called day -1 to -21 before treatment with the combination drugs) and blood will be collected prior to the first dose and a week after the second dose of the drug (day -21, prior to infusion, and day -7). After the 21 days long induction phase, treatment with combination of copanlisib and pembrolizumab will begin and administered in a cyclical manner.  
Phase 1: Phase 1 portion is to determine the dose of copanlisib that is safe and tolerable in combination with pembrolizumab. If you are in this cohort, you will be administered a fixed dose of pembrolizumab (200 mg on day 1 of each cycle) and the dose of copanlisib will depend on the dose level at which you enter the study. It could either be 45 mg on day 1 or 45 mg on day 1 and day 8 or 60 mg on day 1 or day 8 of each cycle. Each cycle is 21 days long. Phase 2: If you are enrolled in phase II portion you will be administered pembrolizumab 200 mg on day 1 of each cycle and copanlisib will be administered as determined to be safe and tolerable from phase 1 position. Each cycle is 21 days long.

If the exams, tests and procedures show that you can be in the research study, and you choose to take part, then you will need the following tests and procedures. They are part of regular cancer care, but may be done more often because you are in this research study.  
Physical exam which will include weight and vital signs We will ask you about your ability to perform daily activities We will ask you about the medicines you are taking or have recently taken (over-thecounter medications, supplements, prescription medications or illegal drugs).  
We will ask you about all the side-effects that you may be experiencing Routine blood tests (about 1 tablespoon)
Research blood tests (about 2-3 teaspoons)
o These samples will be used to discover ways that the study drug does or does not work to shrink tumors o Other additional biomarkers which may impact how individuals respond to the study drug may also be studied A blood sample will be collected for genetic research o Your blood sample contains genes, which are made up of DNA (deoxyribonucleic acid) and which serve as the "instruction book" for the cells that make up our bodies o Genetic research is the study of DNA variation. Variation in your DNA can affect the way you respond to drug treatments o The Sponsor will look at variation in your DNA. Your DNA will be used to understand how genetics affect response to the treatment(s) administered o Your blood may also be used to help develop new tests. The results are for research use only A PET/CT scan or CT scan of your tumor Blood test, once every cycle, to check the presence of a virus (CMV), only if the virus was detected in the test done at the time of the screening Blood will be collected (1 teaspoon) to test your thyroid function

Follow-up Visits:
We will need to schedule a visit about 30 days after your last dose to see if you are experiencing any side effects from the treatment After the first follow up, you will continue to come in for a follow-up visits about every 12 weeks for up to two years or documentation of progression of your disease, whichever happens earlier, about every 26 weeks for the third year, and then about every 3 to 6 months for the rest of your life or until the study ends.  
If your cancer gets worse or you start a new treatment for your cancer, we would like to contact you by telephone about every 12 weeks for three years. After the third year, we would like to contact you about every 6 months.  
Tests and Procedures During the follow-up visits we would like to perform the following tests and procedures:
We will ask you about all the side-effects that you may be experiencing Physical exam which will include weight and vital signs We will ask you about your ability to perform daily activities Routine blood tests (about 1 tablespoon)
Research blood tests (about 2-3 teaspoons)
Blood for (1 teaspoon) thyroid function test Tumor imaging - if you discontinued the study treatment for reasons other than worsening of your disease
Clinical trial: NCT02535247
Section: Purpose of Research
Subsections: Why Is This Research Study Being Done?

This is a research study to test an investigational drug, pembrolizumab, also known as MK-3475 alone or in combination with the investigational drug copanlisib for treatment of NK and T-cell Non-Hodgkin lymphoma. Pembrolizumab is FDA approved for use in other cancers, such as melanoma, lung cancer and head and neck. Copanlisib is also FDA approved for use in Follicular Lymphoma (a type of cancer). Your study doctor will discuss what drugs are approved and available as treatment for your cancer. The study doctor will discuss with you any reasons why you may not be allowed to take part in this research study. We do not know if you will benefit from this research study. It is possible that your condition will get better, but it is also possible that there will be no effect on your condition or that your condition will get worse. We can use what we learn from this research study to help other people with the same disease.
Clinical trial: NCT02535247
Section: Withdrawal from Study
Subsections: Can You Stop Being In The Research Study?|Can You Be Removed From This Research Study?

Yes. Your participation in this research is completely voluntary. If you agree to participate now and change your mind later, you may withdraw at any time. Tell the study doctor if you are thinking about stopping or decide to stop. He or she will tell you how to stop safely and will discuss with you options for withdrawal such as continuing to provide further data collection from routine medical care.

The study doctor may stop you from taking part in this research study at any time if he/she believes it is in your best interest; if you do not follow the research study rules; or if you suffer study related injuries; or if the research study is stopped.