Phase I/II Trial of BINTRAFUSP ALFA (M7824) and Pimasertib for Treatment of Intracranial Metastases
Phase: PHASE1
Conditions: Anatomic Stage IV Breast Cancer AJCC v8, Clinical Stage IV Cutaneous Melanoma AJCC v8, Hematopoietic and Lymphoid Cell Neoplasm, Hormone Receptor Positive Breast Adenocarcinoma, Metastatic Lung Non-Small Cell Carcinoma, Metastatic Malignant Neoplasm in the Brain, Metastatic Malignant Solid Neoplasm, Metastatic Melanoma, Metastatic Triple-Negative Breast Carcinoma, Pathologic Stage IV Cutaneous Melanoma AJCC v8, Prognostic Stage IV Breast Cancer AJCC v8, Stage IV Lung Cancer AJCC v8, Stage IVA Lung Cancer AJCC v8, Stage IVB Lung Cancer AJCC v8
Sponsor: M.D. Anderson Cancer Center

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BINTRAFUSP ALFA (M7824)+Pimasertib in Brain Mets 
University of Texas MD Anderson Cancer Center 
2019-1091, Version 5 
MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2019-1091 
Protocol Title 
Phase I/II Trial of BINTRAFUSP ALFA (M7824) and Pimasertib for 
Treatment of Intracranial Metastases 
Protocol Phase 
I/II 
Protocol Version 
5 
Version Date 
09/26/2023 
Protocol PI 
Hussein Tawbi, MD, PhD 
Department 
Melanoma Medical Oncology 
Investigational 
Products 
BINTRAFUSP ALFA (M7824) and Pimasertib 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
151629 
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BINTRAFUSP ALFA (M7824)+Pimasertib in Brain Mets  
University of Texas MD Anderson Cancer Center 
2019-1091, Version 5 
  
 
 
 
 
 
 
 
 
 
 
                    PROTOCOL 
TITLE: Phase I/II Trial of BINTRAFUSP ALFA (M7824) and Pimasertib for 
Treatment of Intracranial Metastases 
 
STUDY NUMBER: MDACC: 2019-1091 
  
 
VERSION NUMBER: Version 5 
 
PROTOCOL DATE: 26 September 2023 
 
TEST PRODUCTS: BINTRAFUSP ALFA (M7824) 
Pimasertib 
 
  
 
PRINCIPAL 
INVESTIGATOR: 
Hussein Tawbi, MD, PhD 
Associate Professor 
Melanoma Medical Oncology 
Email: HTawbi@mdanderson.org 
 
Jing Li, MD, PhD 
Associate Professor 
Radiation Oncology 
E-mail:  Jing.Li@mdanderson.org 
 
 
 
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BINTRAFUSP ALFA (M7824)+Pimasertib in Brain Mets  
University of Texas MD Anderson Cancer Center 
2019-1091, Version 5 
  
 
Co-INVESTIGATOR: 
 
 
 
Mehmet Altan, M.D. 
Assistant Professor 
Thoracic/Head and Neck Medicine 
E-mail:  MAltan@mdanderson.org 
 
Rashmi Murthy, MD 
Assistant Professor 
Breast Medical Oncology 
Email: rmurthy@mdanderson.org 
 
 
Jeffrey S. Wefel, PhD 
Associate Professor 
Neuropsychology 
E-mail:  Jwefel@mdanderson.org 
 
William A. Murphy, Jr. M.D. 
Professor 
Diagnostic Radiology 
Email: wmurphy@mdanderson.org 
 
                   SUPPORTING COMPANY:                      EMD SERENO, INC 
 
                    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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BINTRAFUSP ALFA (M7824)+Pimasertib in Brain Mets  
University of Texas MD Anderson Cancer Center 
2019-1091, Version 5 
  
 
TABLE OF CONTENTS 
TRIAL SUMMARY ........................................................................................................................ 7 
1.0  Background information ..................................................................................................... 10 
1.1 
Disease Background:  Brain Metastases ........................................................................ 10 
Disease Background: Radiation Therapy for Brain Metastases ................................................. 10 
1.2  Disease Background:  Brain Metastases and Melanoma .................................................... 12 
1.3  Disease Background:  Brain Metastases and breast cancer................................................. 14 
1.4 Disease Background:  Brain Metastases and Lung Cancer .................................................. 15 
1.5  
PIMASERTIB .................................................................................................................... 16 
2.0  
RATIONALE For the Study .......................................................................................... 17 
3.0  Study design .......................................................................................................................... 18 
4.0  OBJECTIVES ........................................................................................................................ 20 
4.1 
Primary Objective ........................................................................................................ 20 
4.1.1 Phase I Primary Objective .......................................................................................... 20 
4.1.2 Phase II Primary Objective ......................................................................................... 20 
4.2 
Secondary Objectives ................................................................................................... 21 
4.3 
Exploratory Objective ................................................................................................. 21 
5.0 Patients .................................................................................................................................. 21 
5.1 
Inclusion Criteria ......................................................................................................... 22 
5.2 
Exclusion Criteria ........................................................................................................ 24 
6.0 Trial Treatment ...................................................................................................................... 26 
6.1 
BINTRAFUSP ALFA (M7824) ................................................................................... 26 
6.1.1 Dosage and Administration ......................................................................................... 26 
6.2 
Pimasertib ..................................................................................................................... 27 
6.2.1 Dosage and Administration ......................................................................................... 28 
6.2.3 Dose Modification ........................................................................................................ 29 
6.2.4 SRT and Dose Interruptions ....................................................................................... 39 
6.2.5 Resumption of Treatment after Dose Delay .............................................................. 40 
6.2.6 Concomitant and Excluded Therapies ....................................................................... 40 
6.2.7 Acceptable Concomitant Medications ........................................................................ 40 
6.2.8 Permitted Therapies: SRT .......................................................................................... 41 
6.2.9 Permitted Therapy for Brain Edema ......................................................................... 41 
6.2.10  Permitted Therapy: Brain Surgery ........................................................................... 41 
7.0 Prohibited Concomitant Medications ..................................................................................... 41 
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BINTRAFUSP ALFA (M7824)+Pimasertib in Brain Mets  
University of Texas MD Anderson Cancer Center 
2019-1091, Version 5 
  
 
Special Precautions .............................................................................................................. 43 
8.0 Study Assessments ...................................................................... Error! Bookmark not defined. 
8.1 
Adverse Event (AE) Monitoring ...................................... Error! Bookmark not defined. 
8.2 
Informed Consent ............................................................. Error! Bookmark not defined. 
8.3 
Physical Examination ....................................................... Error! Bookmark not defined. 
8.3.1 Full Physical Exam............................................................ Error! Bookmark not defined. 
8.3.2 Directed Physical Exam .................................................... Error! Bookmark not defined. 
Eastern Cooperative Oncology Group (ECOG) Performance ScaleError! Bookmark not defined. 
8.3.3 Vital Signs .......................................................................... Error! Bookmark not defined. 
8.3.4 Response Assessment ........................................................ Error! Bookmark not defined. 
8.4 
Archival Tumor Tissue Sample ....................................... Error! Bookmark not defined. 
8.5 
Biopsy ................................................................................. Error! Bookmark not defined. 
8.6 
Laboratory Assessments ................................................... Error! Bookmark not defined. 
8.7 
Electrocardiogram ............................................................ Error! Bookmark not defined. 
8.8 
Neurological Function Testing ......................................... Error! Bookmark not defined. 
ECOG Evaluation ..................................................................... Error! Bookmark not defined. 
8.9 
Research Sample Collection ............................................. Error! Bookmark not defined. 
8.9.1 Tissue .................................................................................. Error! Bookmark not defined. 
8.9.2 Blood ................................................................................... Error! Bookmark not defined. 
Additional Local Testing .......................................................... Error! Bookmark not defined. 
8.9.3 Cerebrospinal Fluid (CSF) ............................................... Error! Bookmark not defined. 
8.10 
Tumor Imaging and Assessment of Disease .................... Error! Bookmark not defined. 
8.11 
Therapy Administration ................................................... Error! Bookmark not defined. 
8.12 
Management of Patients with disease progression .............. Error! Bookmark not defined. 
8.13 
Supportive Care Guidelines ............................................. Error! Bookmark not defined. 
8.14 
Patient Discontinuation .................................................... Error! Bookmark not defined. 
8.15 
Withdrawal ........................................................................ Error! Bookmark not defined. 
8.16 
End of Study ...................................................................... Error! Bookmark not defined. 
8.17 
Post Study Drug Follow up .............................................. Error! Bookmark not defined. 
8.18 
Lost to Follow-up .............................................................. Error! Bookmark not defined. 
8.0 Schedule of Assessments ...................................................................................................... 45 
9.0  Statistical Considerations ....................................................................................................... 51 
9.1 
Phase I ........................................................................................................................... 64 
9.2 
Phase II ......................................................................................................................... 65 
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BINTRAFUSP ALFA (M7824)+Pimasertib in Brain Mets  
University of Texas MD Anderson Cancer Center 
2019-1091, Version 5 
  
 
9.3 
Response Definitions .................................................................................................... 66 
9.3.1 Overall Survival ........................................................................................................... 66 
9.3.2 Intracranial Progression Free Survival ..................................................................... 66 
9.3.3 Toxicity .......................................................................................................................... 66 
9.3.4 Extracranial Progression ............................................................................................. 66 
9.3.5 Extracranial Response Rate ........................................................................................ 66 
9.3.6 Duration of Response ................................................................................................... 67 
9.3.7 Steroid Requirements .................................................................................................. 67 
9.3.8 Other Endpoints ........................................................................................................... 67 
10.0 Assessment of Safety ............................................................................................................. 67 
10.1 
Adverse Event Assessment and Reporting ................................................................ 67 
10.2 
Serious Adverse Events ............................................................................................... 70 
10.3 
Events of Clinical Interest ........................................................................................... 72 
10.4 
Definition and Reporting of an Overdose for This Protocol .................................... 73 
10.5 
Reporting of Pregnancy and Lactation ...................................................................... 73 
11.0 Administrative and Regulatory Details .................................................................................. 73 
11.1 
Investigator Communications ..................................................................................... 73 
11.2 
Investigator Responsibility for Reporting Events ..................................................... 74 
11.3 
Data Management ........................................................................................................ 74 
11.3.1   Data Collection ........................................................................................................... 74 
11.3.2   Data Safety Monitoring Plan .................................................................................... 74 
11.3.3     Data Handling and Record Keeping ...................................................................... 75 
Institutional Review Board (IRB) Approval.......................................................................... 75 
Compliance with Trial Registration and Results Posting Requirements ............................ 75 
11.3.4    Ethical Considerations .............................................................................................. 76 
11.3.5 Informed Consent ........................................................................................................ 76 
12.0 Study Documentation, Monitoring, and Administration ........................................................ 76 
Appendices ..................................................................................................................................... 77 
Contraception Requirements .................................................................................................. 86 
Pregnancy Testing .................................................................................................................. 88 
13.0 References ............................................................................................................................. 95 
 
 
 
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BINTRAFUSP ALFA (M7824)+Pimasertib in Brain Mets  
University of Texas MD Anderson Cancer Center 
2019-1091, Version 5 
  
 
TRIAL SUMMARY 
 
Title of Study 
Phase I/II Trial of Bintrafusp Alfa (M7824) and Pimasertib for 
Treatment of Intracranial Metastases 
 
Protocol Number 
2019-1091 
Principal Investigator 
Hussein Tawbi, MD, PhD 
Project Phase 
Phase 1/2 
Number of Study 
Center(s) 
1 
Objectives 
Phase I Primary Objective 
 
• 
Establish safety profile and recommended phase II dose for combining Bintrafusp Alfa 
(M7824) and pimasertib in patients with brain metastases. 
Phase II Primary Objective 
• 
Time to intracranial progression (defined as progression of existing lesions and development 
of new lesions by modified RECIST 1.1) and Overall survival. 
Secondary Objectives 
• 
Intracranial progression 4, 8, 12, 16 weeks and every 8 weeks thereafter.  
• 
Intracranial objective response rate as measured by RANO-BM, iRANO, and 
RECIST 1.1. 
• 
Time to second intracranial progression after Salvage SRS  
• 
Overall survival rate at 24, 52, 68 weeks. 
• 
Frequency of grade 3+ intracranial toxicities at 4, 12, 24, 36, 52, and 68 weeks.. 
• 
Frequency of extracranial progression and response rate at 8, 16, 24, and every 8 
weeks thereafter. 
• 
Frequency of neurocognitive decline at 24, 52, and 68 weeks (optional). 
• 
Changes in neurocognitive function and health-related quality of life. 
• 
Dose, duration and frequency of steroid use for symptomatic management. 
Exploratory Objectives 
• 
Identify molecular and/or immunological markers from biospecimens (tissue, 
blood, and CSF) that are associated with treatment response and toxicity. 
• 
Identify imaging biomarkers of response and toxicity (acute radiation 
effect/radionecrosis and neurocognitive changes) from multiparametric MRI 
and/or delayed PET that predict treatment response and toxicity.  
• 
Dose, duration and frequency of steroid use for symptomatic management. 
• 
To evaluate the potential correlation between mutational burden and tumor response 
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BINTRAFUSP ALFA (M7824)+Pimasertib in Brain Mets  
University of Texas MD Anderson Cancer Center 
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Study Design 
• 
Identify correlative or surrogative relationship between systemic (blood) 
and imaging markers and treatment outcomes. 
This study is an open-label Phase I/II trial to determine the safety and efficacy of pimasertib 
in combination with Bintrafusp Alfa (M7824) in patients with brain metastases. The Phase I 
study will accrue patients with melanoma, lung, and breast cancers to a dose escalation phase 
as described below. The Phase II study will include expansion cohorts, of 10 patients each 
with melanoma, lung, breast brain metastases, to better characterize the safety profile and 
efficacy of the combination and its impact on time to intracranial progression. 
 
We have also incorporated an early imaging time point to allow the application of stereotactic 
radiosurgery (SRS) to intracranial lesions that are either progressing or not responding. This 
decision will be made in the context of multi-disciplinary care provided at the MD Anderson 
Brain Metastasis Clinic. 
 
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BINTRAFUSP ALFA (M7824)+Pimasertib in Brain Mets  
University of Texas MD Anderson Cancer Center 
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Key Inclusion Criteria (Please see section 5.1 for complete eligibility criteria) 
1. Age ≥ 18 years old. 
2. Life Expectancy > 12 weeks. 
3. Subjects must be willing and able to comply with scheduled visits, 
treatment  schedule, laboratory testing, and other requirements of the 
study. 
4. At least one measurable untreated brain lesion ≥ 0.5 cm and <3.0 cm in the 
 longest axis according to modified RECIST 1.1. 
5. Prior SRS with up to 10 lesions treated with at least a 14 day interval is   
      allowed as long as the previous treatment volume does not overlap with the   
      current targets.  The target could be a previously irradiated lesion with clear 
evidence of progression. 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Subjects must be free of neurologic signs and symptoms related to 
metastatic brain lesions and must not have required or received systemic 
corticosteroid therapy in the 10 days prior to beginning protocol therapy. 
8. Prior treatment with immunotherapy and targeted therapy allowed as long 
as it did not include a combination of MEKi + anti-PD(L)-1 antibody and is 
>14 days prior to start of protocol therapy. All tumor types will be eligible 
and included in the dose escalation phase. Dose expansions will include 10 
patients each from lung, breast, and melanoma. 
9. Patients with melanoma must have received prior PD-1 based therapy. 
10. Patients with NSCLC must have received prior PD-1 based therapy. 
11. Patients with TNBC and HR+ are included (any number of prior lines of 
therapy- including IO naïve patients).   
12. For HR+ patients, patients are allowed to receive endocrine therapy 
(Arimidex, letrozole, exemestane, or fulvestrant). Concurrent CDK4/6 
inhibitors will not be allowed.  
13. Systematic radiation therapy is allowed (>14 day washout)  
14. Prior platinum-based chemotherapy for NSCLC patients is allowed  
 
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 Bintrafusp Alfa (M7824)+Pimasertib in Brain Mets  
University of Texas MD Anderson Cancer Center 
MDACC Protocol Number, Version 5 
  
 9 
 
 
                                                                                       Exclusion Criteria 
 
1. 
Patients with clinical or radiographic evidence of leptomeningeal disease. 
2. 
Those who experienced grade 3 or 4 neurotoxicity from prior SRS. 
3. 
Contraindications to MRI (implanted metal device or foreign bodies) or MRI contrast (insufficient 
renal function or allergy). 
4. 
Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully 
comply with study therapy or assessments should not be enrolled. 
5. 
Active secondary malignancy unless the malignancy is not expected to interfere with the evaluation of 
safety and is approved by the PI. Examples of the latter include basal or squamous cell carcinoma of 
the skin, in-situ carcinoma of the cervix, and isolated elevation of prostate-specific antigen. Subjects 
with a completely treated prior malignancy and no evidence of disease for ≥ 2 years are eligible. 
6. 
Has a known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or 
known active hepatitis C virus infection (note treated and cured history of hepatitis C is 
allowed)(hepatitis C virus [HCV] RNA [qualitative] is detected). Note: Without known history, testing 
needs to be performed to determine eligibility. Hepatitis C antibody (Ab) testing is allowed for 
screening purposes in countries where HCV RNA is not part of standard of care. 
7. 
Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required 
unless mandated by local health authority. 
8. 
The use of corticosteroids is not allowed for 10 days prior to initiation of therapy (based upon 5 times 
the expected half-life of dexamethasone) except patients who are taking steroids for physiological 
replacement. If alternative corticosteroid therapy has been used, consultation with the PI is required to 
determine the washout period prior to initiating study treatment. 
9. 
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily 
prednisone equivalent) or other immunosuppressive medications within 14 days of study initiation. 
Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone 
equivalent, are permitted in the absence of active autoimmune disease. 
10. Major surgical procedure, open biopsy (excluding skin cancer resection), or significant traumatic 
injury within 14 days of initiating study drug (unless the wound has healed) or anticipation of the need 
for major surgery during the study. 
11. Non-healing wound, ulcer. 
12. Women who are breast-feeding or pregnant.  
13. Subjects with a history of serious intercurrent chronic or acute illness, such as cardiac or pulmonary 
disease, hepatic disease, bleeding diathesis or recent major bleeding events or other illness considered 
by the Investigator as high risk for investigational drug treatment 
14. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient 
ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of 
study medication (except for adequately treated catheter-related venous thrombosis occurring more 
than 1 month before the start of study medication). 
15. History of clinically significant cardiac disease or congestive heart failure > New York Heart 
Association (NYHA) class 2. Subjects must not have unstable angina (anginal symptoms at rest) or 
new-onset angina within the last 3 months or myocardial infarction within the past 6 months. 
16. Investigational drug use within 14 days (or 5 half-lives, whichever is longer) of the first dose of 
bintrafusp alfa and/or pimasertib. 
17. Has a history of (Grade 3 or 4) non-infectious pneumonitis that required steroids or current 
pneumonitis. 
18. Retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), 
history of retinal vein occlusion (RVO) or any eye condition that would be considered as risk factor 
for RVO (e.g. uncontrolled glaucoma or ocular hypertension) 
20. 
Creatine phosphokinase level at baseline NCI CTCAE Grade ≥2 (>2.5x ULN – 5x ULN) and/or     
         previous history of myositis or rhabdomyolysis 
21. 
For NSCLC cohort patients whose tumor exhibit activating EGFR mutation, ALK         
          or ROS translocation and have a standard of care molecular targeted therapy     
          available for these mutations, will be excluded from this study. Patients who   
          progressed or could not tolerate these standard of care molecular targeted agents  
         are eligible for this study. Lung adenocarcinoma patients may be consented prior  
          to the EGFR and ALK status being known, but EGFR and ALK status must be  
          determined prior to initiating therapy 
22.     Administration of live, attenuated vaccine therapies for the prevention of infectious diseases within 4   
          weeks prior to day 1 of treatment and during therapy 
 
 
 
 
 
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BINTRAFUSP ALFA (M7824)+Pimasertib in Brain Mets  
University of Texas MD Anderson Cancer Center 
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1.0  
BACKGROUND INFORMATION 
1.1 
DISEASE BACKGROUND:  BRAIN METASTASES 
 
Metastatic tumors to the brain are by far the most common intracranial malignancy, totaling about 170,000 per year and developing in 
about 40% of all advanced cancer patients. Patients with metastatic brain lesions far outnumber patients with primary brain tumors [1-
3].  Patients with advanced malignancies have been surviving longer with improved control of extra-cerebral disease due to new 
targeted and immune therapies. These therapeutic approaches (e.g., anti-PD-1 antibodies and BRAF-targeted therapy in melanoma, 
anti-HER2 in metastatic HER2+ breast cancer, epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors in EGFR-mutated 
non-small cell lung cancer (NSLSC)) [1–3] increase efficacy allowing for improved survival. Indeed the 5-year outcomes from PD-1 
based therapy in melanoma indicate survivals rates of up to 40%, and in NSCLC, the 5-year OS in PD-L1 TPS 50 or above is 25%. 
[56] Hence, the incidence of brain metastases has been increasing.  Additionally, other factors may contribute, including improved 
detection of small metastases by magnetic resonance imaging (MRI).  Nonetheless, the incidence of BMs depends on the type of 
primary cancer, varying from approximately 5–50%.[4] CNS involvement occurs more commonly in lung cancer, breast cancer, 
melanoma, and renal cell carcinoma patients.[4] Metastatic CNS disease can have devastating neurologic effects including focal 
neurologic dysfunction, cognitive dysfunction, seizures, stroke-like symptoms, and death. The features that impact outcome of brain 
metastases include their primary histology, number, size and site of brain metastases, the status of extra-cranial disease, and the 
performance status of the patient. BMs are associated with a poor prognosis. Overall survival varies according to the tumor types and 
tumor subtypes from 3 to 25 months.[4 ] 
 
Novel therapeutic approaches are direly needed, and consideration needs to be made for combination of effective therapies including 
targeted agents, immunotherapy, with radiation therapy. 
DISEASE BACKGROUND: RADIATION THERAPY FOR BRAIN METASTASES  
CNS directed therapies including surgery, stereotactic radiosurgery (SRS) (gammaknife (GK), or whole brain radiation therapy (WBRT) 
have been the mainstay of therapy. However, the optimal treatment of multiple brain metastases is not well defined and still very 
inadequate. The paucity of data in the management of CNS metastases is further highlighted as patients with symptomatic brain 
metastases are often excluded from participation in clinical trials, thereby further limiting outcomes data in this patient population. Many 

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BINTRAFUSP ALFA (M7824)+Pimasertib in Brain Mets  
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patients who have controlled systemic disease frequently develop progressive or recurrent brain metastases.  For these patients, no single 
standard of care option for treatment exists.  
Radiation is commonly utilized to treat brain metastases via WBRT or SRS. WBRT can be conducted utilizing a number of different 
treatment machines and is most typically performed with a conventional linear accelerated. WBRT is given through a fractionated 
schedule with a typical regime being 30 Gy in 10 fractions. WBRT has limited efficacy and impacts poorly on the quality of life. WBRT 
is associated with significant side effects and complications, with cognitive decline, including memory loss, impaired executive function 
and speed of processing, being the most feared one, and these late complications are usually irreversible. A recent clinical trial has 
demonstrated at least 65% probability of significant cognitive decline at 24 weeks associated with WBRT.[5] In addition, WBRT causes 
a minimum of 4-6 weeks interruption of systemic therapy, which can lead to progression of systemic disease and worse survival.[6] As 
a result, there has been vigorous effort in recent years to improve treatment of brain metastasis. The outcomes of 86 melanoma patients 
with brain metastases were widely varied: in those treated with WBRT alone, the median survival was 3 months; in those treated with 
SRS, the median survival was 7 months; and surgery was associated with a median survival of 11-12 months [27].  
Stereotactic radiosurgery (SRS) is a type of external radiation therapy that uses multiple beams to deliver a large dose of radiation to a 
tumor in a single session. SRS is conducted via a number of possible modalities including Gamma Knife or a conventional linear 
accelerator. Treatment is either as a single fraction or hypofractionated (within 3-5 fractions). Generally speaking, SRS is utilized to 
treat a limited number of brain metastases while WBRT is utilized to treat more widespread disease. However, the definition of what 
constitutes limited versus widespread continues to evolve. SRS is highly preferred and can be utilized in 1-3 metastases according to 
NCCN guidelines; however in practice, SRS is frequently utilized in patients with many more brain lesions [8]. The use of 
immunotherapy may complement radiation therapy because the latter damages the blood brain barrier (BBB), alters the tumor 
microenvironment, and increases immunogenicity of tumors. 
Two phase III trials in patients with 1-3 brain metastases, one conducted at MD Anderson [9] and one through a cooperative group,[10] 
have established SRS as the standard care in this patient population.  Currently we are investigating whether the use of SRS can be 
expanded to patients with more brain metastases in a phase III trial randomizing patients with 4-15 brain metastases to SRS vs. WBRT 
(NCT01592968).  
There is pre-clinical and clinical data suggesting clinical activity of systemic anti-neoplastic therapies, including immunotherapies and 
targeted therapies. One of the challenges of treating brain metastases is the blood-brain barrier leading to poor permeability of many 
drugs. The blood-brain barrier is a highly selective permeability barrier comprised of capillary endothelial cells, which are connected 
by tight junctions and astrocyte foot processes that limit diffusion of molecules and drugs into the CNS compartment [11, 12]. 

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Additionally, as brain metastases tend to occur later in the disease course, these tumors may be biologically and genomically distinct 
from the primary site or extracranial metastatic sites and may be more resistant to cytotoxic and targeted therapies [13, 14]. 
 
1.2  DISEASE BACKGROUND:  BRAIN METASTASES AND MELANOMA 
 
Cutaneous malignant melanoma is the most aggressive form of skin cancer, accounting for the large majority of skin cancer-related 
deaths.  The global incidence continues to rise, with current estimates of 132,000 new diagnoses/year and 37,000 deaths [29]. Melanoma 
accounts for ~5% of all new cases of cancer in the United States (US). The incidence of melanoma continues to rise by almost 3% per 
year in the US. In 2016, there will be an estimated 76,380 new melanoma patients and 10,130 melanoma-related deaths in the USA.[29] 
Melanoma is one of the few tumors whose incidence is still increasing, despite being preventable with appropriate sun protection. The 
majority of patients present with localized disease and their prognosis is excellent if primary tumors are 1.0 mm or less in thickness. 
However, when there is lymph node involvement, survival rates are roughly halved due to the significant increase in the risk of distant 
systemic metastases including to lung, liver, and brain. Patients with metastatic disease historically face long-term survival rates of less 
than 10%, although this scenario is dramatically changing after the emergence of groundbreaking systemic therapies, including BRAF 
and MEK inhibitors for patients harboring a BRAF mutation, immunotherapeutic agents such as Cytotoxic T-Lymphocyte Antigen 4 
(CTLA4) inhibitors and especially Programmed Death 1 (PD-1) inhibitors.[5-11] Long-term remissions are being increasingly observed 
in patients that respond to therapy, bringing new hope and excitement to the field. 
 
Population studies demonstrate cutaneous melanoma is the third most common cause of brain metastasis development only after the 
lung and breast cancer, reflecting its distinctive neurotropism.[30-32] Approximately 40-50 % of stage IV melanoma patients eventually 
develops clinical manifestations of melanoma brain metastasis (MBM).[33] The prevalence is likely higher as autopsy series have 
reported 55–75 % of melanoma patients have MBM.[34, 35] Although outcomes differ for patients with MBM, overall prognosis 
remains poor. The overall survival reflects the effects of therapy on both intracranial and extracranial disease at the time of presentation 
and may not be entirely representative of intracranial disease control. Even with early diagnosis and aggressive local therapy, MBM is 
the cause of death in nearly 95 % of patients.[31] The bleak outcomes of MBM have not been mitigated over the past three decades, and 
although the last 4 years have brought tremendous promise for patients with metastatic melanoma, this has not yet translated into 
improved outcomes for MBM, since these patients have been systematically excluded from the vast majority of clinical trials of 
investigating systemic therapy.  
 

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The management of MBM has been traditionally limited to surgical or radiotherapy approaches. However, melanoma is a relatively 
radiation-resistant tumor; as melanoma cells were shown in early in vitro studies to have a low responsiveness to radiation, which 
corresponded with documented low efficacies of WBRT in clinical use.[36]   Patients with MBMs who underwent WBRT treatment 
alone even in the early 2000’s had a median survival of only 3.4 months compared with 2.1 months if they received supportive care 
alone.[37-40] Given this limited benefit, WBRT use is generally limited to MBM patients with no surgical options, symptomatic diffuse 
disease, large volume single lesions or leptomeningeal spread of disease. In contrast to the limited role of WBRT, SRS has emerged as 
a highly effective local therapeutic approach to MBM treatment.  Since the studies performed by Patchell et al.[30, 31] in the 1990’s, 
the overall management of brain metastases has changed significantly.   The added value of WBRT to SRS is questionable; a randomized 
trial involving multiple tumor types showed that intracranial metastatic control following WBRT+SRS was not significantly different 
than after SRS alone, and OS was also equivalent.[41] Additionally, the response of brain metastases was independent of cancer type 
and previously designated radio-resistance.[42] Further, a small study comparing WBRT alone to WBRT+SRS was stopped early due 
to a 1-year local failure rate of 100% in those undergoing WBRT alone versus only an 89% failure rate in those undergoing 
WBRT+SRS.[43] SRS alone has therefore now become the standard treatment for the majority of patients with limited MBMs.    
 
Systemic therapy has not been used effectively. Discovery of driver mutations in RAS-MAP-kinase signaling pathway has led to the 
development of agents targeting specific enzymes including BRAF and MEK. Single-agent BRAF inhibitors dabrafenib and 
vemurafenib have been proven safe to administer in patients with BRAF-mutated melanoma and active MBM and have activity that 
parallels extracranial activity with objective intracranial response rate (OIRR) of 35-42%.[45, 46] Still, progression-free and overall 
survivals are still lower for this population than for patients with only extracranial metastases, with few systemic alternatives for patients 
after progression. Furthermore, BRAF mutation is only detected in about half of melanoma patient. The combination of BRAF inhibitor 
dabrafenib and MEK inhibitor trametinib is being evaluated for active melanoma brain metastasis in a clinical trial (ClinicalTrials.gov 
Identifier: NCT02039947).  
 
The recent approval of immunotherapeutic agents has also brought some enthusiasm for this population. Single-agent ipilimumab has 
been proven safe and at least as effective intracranially versus (vs) extracranially, but still with low response rates (up to 16%), and 
mostly in asymptomatic patients.[20] Pembrolizumab was studied in 18 patients with untreated or progressive MBM, with 4 durable 
responses (22%), including 2 complete responses.[21] This promising activity from immunotherapy in brain metastasis, however, is 
restricted by the requirement of no systemic corticosteroids to achieve maximal benefit, as was the case with ipilimumab, which can 
pose a problem since corticosteroids can be crucial to managing perilesional edema in the brain. In addition, immunotherapy with PD-
1 antibodies itself can induce further swelling by increasing influx of inflammatory cells. In the study with pembrolizumab, 17% of 
treated patients experienced seizure activity, indicating a potential need for strategies to reduce or limit perilesional edema that do not 
curtail the immunotherapeutic effect. 

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Recent advances in targeted and immunotherapy of melanoma have led to intracranial responses with systemic therapy. Targeted therapy 
with BRAF/MEKi leads to a high rate of intracranial responses similar to extracranial disease albeit of seemingly shorter duration. 
Immunotherapy with combination anti-CTLA4 and anti-PD-1 antibodies has led to high response rates in patients with melanoma brain 
metastases that have the following characteristics: a) clinical responses as early as 6 weeks, b) complete responses in 26% and overall 
objective response rate in 56% of patients, c) durability in >90% of patients, d) high concordance between extracranial and intracranial 
disease, and e) high progression free survival rates of >60% at one year. [53, 54]. 
 
1.3  DISEASE BACKGROUND:  BRAIN METASTASES AND BREAST CANCER 
 
Brain metastases (BMs) are the most common central nervous system (CNS) tumors in adults. The incidence of BMs is increasing due 
to both improved diagnostic techniques (e.g. magnetic resonance imaging: (MRI) and increased cancer patient survival through advanced 
systemic treatment approaches (e.g. anti-HER2 in metastatic HER2 breast cancer, epidermal growth factor receptor (EGFR) tyrosine-
kinase inhibitors in EGFR-mutated non-small cell lung cancer (NSCLC) [23-25]. The incidence of BMs depends on the type of primary 
cancer, varying from approximately 5–50% [4].  CNS involvement occur more commonly in lung cancer, breast cancer, melanoma, and 
renal cell carcinoma patients[4]. BMs are associated with a poor prognosis. Overall survival varies according to the tumor types and 
tumor subtypes from 3 to 25 months[4].  In breast cancer, differences in survival of patients with BMs by tumor subtype (luminal, HER2 
and triple-negative metastatic breast cancer) have been observed and highlight the need for a tailored approach in this patient 
population[5]. Several predicting factors for BMs have been identified to date and include age, histological grade, negative status of 
estrogen receptor, HER2 and number of non-CNS metastatic sites (1 versus >1) [26].   
To date, general indications to use systemic treatments for BMs is limited to highly chemotherapy-sensitive primary tumors, BMs 
from primary tumors with identified molecular alterations amenable to targeted therapy crossing the BBB, asymptomatic BMs found 
on screening MRI with planned systemic treatment, or in cases in which other therapeutic options have been exhausted and there is a 
drug available [7]. This is due to the lack of efficacy of systemic treatment including in breast cancer patients with BMs. 
Consequently, until recently, treatment of BMs from breast cancer was focused on local therapy (surgery or radiotherapy) [27].  
Indeed, adding active systemic therapy to local (radiation, surgery) therapy could be one effective way to improve the outcome of 
patients with BMs. The concept aims to use and to enhance both local and systemic effects of the treatment. The immune stimulatory 
effects of radiation therapy in combination with immunotherapy [e.g. checkpoint inhibitors, CAR (chimeric antigen receptor)-T cell 
[28] is an example of this innovative approach. 

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In breast cancer, differences in survival of patients with BMs by tumor subtype (luminal, HER2 and triple-negative metastatic breast 
cancer) have been observed and highlight the need for a tailored approach in this patient population.[5] Several predicting factors for 
BMs have been identified to date and include age, histological grade, negative status of estrogen receptor, HER2 and number of non-
CNS metastatic sites (1 versus >1).[6]  
 
1.4 DISEASE BACKGROUND:  BRAIN METASTASES AND LUNG CANCER  
Lung cancer is the leading cause of worldwide cancer mortality, and is responsible for more deaths annually in the United States than 
the combination of breast, colorectal, and prostate cancer, with an estimated 1.04 million new cases each year worldwide[15,16].   Non–
small cell lung cancer (NSCLC) accounts for approximately 75% of all lung cancers. Of these, approximately one third will develop 
brain metastasis at some time during the course of their disease. Brain metastases are a common problem in patients with metastatic 
NSCLC. About 7%–10% of NSCLC patients present with brain metastases at the time of initial diagnosis, and as many as 20%–40% of 
patients develop brain metastases at some point during their illness[17-20]. Additionally, 50% of all brain metastases are from lung 
primary tumors[21].  Unfortunately for the vast majority of these patients, this diagnosis is associated with significant morbidity in 
addition to shortened survival.  Present treatments for brain metastases include surgery in select patients with limited intracranial and 
systemic disease burden and good performance status. However, the majority of patients receive treatment for their brain metastases via 
whole brain radiation Therapy (WBRT) and Stereotactic Radiosurgery (SRS).  These modalities are often quite effective in alleviating 
symptoms; however, median survival remains poor, estimated to be between 2-7 months[22]. Clearly new treatments are needed.  
 
Radiation is commonly utilized to treat brain metastases via WBRT or SRS. Generally speaking, SRS is utilized to treat a limited number 
of brain metastases while WBRT is utilized to treat more widespread disease. However, the definition of what constitutes limited versus 
widespread continues to evolve. WBRT can be conducted utilizing a number of different treatment machines and is most typically 
performed with a conventional linear accelerated. WBRT is given through a fractionated schedule with a typical regime being 30 Gy in 
10 fractions. On the other hand SRS is conducted via a number of possible modalities including Gamma Knife or a conventional linear 
accelerator. Treatment is either as a single fraction or hypofractionated (within 3-5 fractions). 
 
 
Therapeutic Agents Background:  BINTRAFUSP ALFA (M7824) and Pimasertib 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information on Bintrafusp Alfa (M7824) and 
Pimasertib.  

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Background on Bintrafusp Alfa (M7824) 
 
Bintrafusp Alfa (M7824) is a novel fusion protein comprised of the extracellular domain of the human TGFβ-RII (transforming growth 
factor beta –receptor II) that is covalently linked to the C-terminus of the heavy chain of the anti-PD-L1 (anti-programmed death ligand 
1) antibody via a flexible (Gly4Ser) 4G linker. The anti-PD-L1 moiety of Bintrafusp Alfa (M7824) is identical to anti-PD-L1 
monoclonal antibody avelumab, except for 3 amino acid substitutions in the heavy chain constant regions that result in a different 
human IgG1 allotype, and one amino acid substitution in the heavy chain for antibody fusion protein stability. As of June 2017, FDA 
has granted accelerated approval to avelumab for metastatic Merkel cell carcinoma (MCC) and locally advanced or metastatic 
urothelial carcinoma whose disease progressed during or following platinum-containing chemotherapy. 
The TGFβRII component functions as a TGFβ neutralizing ‘trap”.  Bintrafusp Alfa (M7824) is designed to target two negative regulatory 
pathways in immunosuppression: the cell-intrinsic one mediated by tumor cell-immune cell interaction, in which programmed death 
ligand-1 (PD-L1)/programmed 
1.5  
PIMASERTIB  
Pimasertib is an orally bioavailable small-molecule inhibitor of MEK1 and MEK2 (MEK1/2) with potential antineoplastic 
activity. Pimasertib selectively binds to and inhibits the activity of MEK1/2, preventing the activation of MEK1/2-dependent 
effector proteins and transcription factors, which may result in the inhibition of growth factor-mediated cell signaling and tumor 
cell proliferation. MEK1/2 (MAP2K1/K2) are dual-specificity threonine/tyrosine kinases that play key roles in the activation of 
the RAS/RAF/MEK/ERK pathway and are often upregulated in a variety of tumor cell types. 
Pimasertib (MSC1936369B) is an orally bioavailable and selective small-molecule inhibitor of MEK1 and MEK2 that prevents the 
activation of MEK1/2-dependent effector proteins and transcription factors [47, 48]. It has demonstrated robust antitumor activity in 
preclinical studies, including tumor growth reduction in murine myeloma xenografts [47] and tumor regression in a mouse model of 
D-MUT colorectal cancer [48] and it has also been shown to circumvent resistance to BRAF inhibition in human melanoma cells [47]. 
Pimasertib given as a single agent showed acceptable toxicity with a maximum tolerated dose (MTD) that depended on the treatment 
schedule in patients with advanced solid tumors [49]; with continuous twice daily administration, the MTD was 75 mg. When 
pimasertib was given in combination with FOLFIRI (5-fluorouracil/folinic acid/irinotecan), the MTD was reached at 45 mg/day in a 5 
days on/2 days off schedule in patients with KRAS-mutated metastatic colorectal cancer [50]. 

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2.0  
RATIONALE FOR THE STUDY 
 
2.1  
 
RATIONALE FOR COMBINING IMMUNOTHERAPY WITH TARGETED THERAPY IN THE TREATMENT OF BRAIN METASTASES 
 
Immunotherapies that target the interactions between antigen presenting cells (APCs), T lymphocytes, and cancer cells to 
potentiate an anti-tumor immune response have been developed, with many recently approved by the FDA for specific 
indications in many advanced malignancies. Over the past few years, immunomodulation has come to be a mainstay in the 
treatment algorithm in many malignancies, including melanoma and NSCLC, and a number of other cancers. 
Nonclinical data show a negative association between MEK activity and active antigen presentation (MHC-1 and II expression) 
that appears to be coupled to simultaneous PD-L 1 expression [51-52]). These findings link the MAPK pathway activation to 
the tumor immune-evasion. Consistently, MEK inhibition results in an increased number of tumor-infiltrating CDS-positive T 
lymphocytes and PD-L 1 and MHC expression [51-52]. These effects are responsible for the enhanced anti-tumor immune 
response observed with the combination of MEK with PD-L 1/PD-1 inhibitors [52]. 
 
The combination of a MEKi with immunotherapy has been studied in preclinical models and confirmed the presence of 
additivity if not synergy. The combination of cobimetinib and atezolizumab has also shown up to 50% ORR in patients with 
melanoma in a Phase I study and has now moved into the Phase III setting. IMspire is a Phase III study currently examining the 
combination of cobimetinib+atezolizumab vs pembrolizumab in patients with BRAF-wt melanoma (NCT03273153). 
 
While there are number of trials looking into every possible combination of targeted therapies and IO, there is no clinical trial 
specifically in NSCLC has been matured yet. [57] 
Standard Treatment for patients with oligo-brain metastases remains stereotactic radiosurgery. In recent years, immunotherapy 
and MEK inhibitors have shown intracranial activity in melanoma patients with brain metastases, raising question on whether 
such intracranial activity from immunotherapy and target agents can have sufficient intracranial activity to hold or delay SRS 
with the goal to minimize SRS treatment toxicity, without compromising patients’ survival or intracranial control. 
 
Pimasertib has excellent BBB penetration and can overcome one of the major issues facing other MEKi. Finally, using a bispecific 
PD-L1 and TGFβ neutralizing ‘trap” tackles 2 potential mechanisms of resistance to immunotherapy that are relevant for melanoma, 
breast, and lung cancers. 

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The goal of this combination is ultimately to seek synergy between MEK inhibition and the dual inhibition of PD-1/PD-L1 pathway 
and TGFbeta. It is also conceivable that potentiating the immune response, while augmenting tumor response, could also result in a 
higher rate of toxicities. At one level, immune-related toxicities could be augmented with specific attention being paid to pneumonitis 
and liver dysfunction. While the mechanism by which MEK inhibitors cause pneumonitis is distinct, it could still be perpetuated in the 
presence of an immune response. We will follow patiens closely for those events and manage promptly. Another potential overlapping 
toxicity is uveitis. However, MEKi have been combined safely with anti-PD-L1 previously as in the Phase III study of 
cobimetinib+atezolizumab +/- regorafenib in colorectal cancer [58].  
 
2.2  
Rationale for combining immunotherapy with stereotactic radiosurgery (SRS) in the treatment of brain metastases 
There is pre-clinical and clinical data suggesting clinical activity of systemic anti-neoplastic therapies, including immunotherapies and 
targeted therapies. One of the challenges of treating brain metastases is the blood-brain barrier leading to poor permeability of many 
drugs. The blood-brain barrier is a highly selective permeability barrier comprised of capillary endothelial cells, which are connected 
by tight junctions and astrocyte foot processes that limit diffusion of molecules and drugs into the CNS compartment [48, 49]. 
Additionally, as brain metastases tend to occur later in the disease course, these tumors may be biologically and genomically distinct 
from the primary site or extracranial metastatic sites and may be more resistant to cytotoxic and targeted therapies [50]. 
Radiation, in addition to providing effective local treatment through its tumoricidal effect via generation of DNA double strand breaks, 
has been found in recent years to trigger an immune response, leading to improved local control and abscopal effect (tumor regression 
in non-irradiated sites).  This is achieved through radiation induced tumor neoantigen release, MHC class I expression, and pro-
inflammatory cytokine release. Additionally, radiation has been found to modulate the immune suppressive tumor microenvironment 
by altering cell adhesion and immunomodulatory molecules and downregulating the suppressive cytokine effects. The best radiation 
regimen in inducing or supporting immune response is yet to be identified. Although stereotactic radiosurgery (SRS), which delivers 
high dose radiation in a single fraction was thought to generate the most robust immune response,  recent pre-clinical study demonstrated 
that fractionated stereotactic radiation therapy (FSBRT), where radiation is delivered in 3-5 fractions, had better immune modulating 
effect through the STING pathway and induction of IFN-I. It would be of great importance to identify the best immune-promoting 
radiation regimen and to gain further knowledge on how radiation can interact with other CNS-penetrant small molecules to modulate 
tumor microenvironment and to enhance tumor killing. 
3.0  
STUDY DESIGN 
 

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This study is an open-label Phase I/II trial to determine the safety and efficacy of pimasertib in combination with Bintrafusb Alfa 
(M7824) in patients with brain metastases. The Phase I study will accrue patients with melanoma, lung, and breast cancers to a dose 
escalation phase as described below. The Phase II study will include expansion cohorts, of 10 patients each with melanoma, lung, and 
breast brain metastases, to better characterize the safety profile and efficacy of the combination and its impact on time to intracranial 
progression. 
 
We have also incorporated an early imaging time point to allow the application of SRS to intracranial lesions that are either 
progressing or not responding. This decision will be made in the context of multi-disciplinary care provided at the MD Anderson 
Brain Metastasis Clinic. 
 
Phase I: 
The phase I dose finding part of the study is to determine the recommended phase II dose (RP2D) of Bintrafusp Alfa (M7824) + 
pimasertib in patients with intracranial metastasis. The planned DL1 and DL2 doses are Bintrafusp Alfa (M7824) flat dose of 1200 mg 
every 2 weeks and pimasertib 45 mg PO BID (Dose Limit or DL1) and 60 mg PO BID (DL2), and fallback doses DL-1 are Bintrafusp 
Alfa (M7824) flat dose of 1200 mg every 2 weeks and Pimasertib at 30 mg PO BID. Every cycle will be 28 days. We will enroll up to 
12 patients to the Phase I portion (18, should the trial de-escalate to DL-1). The standard “3+3” design will be employed to determine 
the RP2D. If DL1 is considered too toxic, DL-1 will be explored; if unacceptable toxicity is observed at DL-1, alternative dose 
schedules may be evaluated in an amendment.  The recommended phase II dose (RP2D) is defined as the highest dose level with no 
more than 1 patient with DLT out of 6 patients that are treated.  Please note that the study plans on enrolling up to 2 cohorts in Phase 1 
of the trial (the 45mg and either the 30 or 60 mg, depending on the safety of Cohort 1).   
 
Phase II: 
The purpose of phase II part is to estimate the time to intra-cranial progression and overall survival time.  In this part, we will enroll 
up to 24 patients into RP2D.  The 6 patients treated at RP2D from phase I part of the study will be included in the Phase II part, thus 
resulting in a total of 30 patients at RP2D by the end of the study, with the goal of having 10 patients each of melanoma, NSCLC, and 
breast cancer. This phase II part is designed to collect data for future larger studies.  Specifically, we would like to estimate time to 
intracranial progression considering death as a competing risk and overall survival time using Kaplan-Meier method, both with 95% 
confidence interval. 
 
 
 
 

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Figure 1:  Study Schema 
 
 
 
 
 
DL-1 
30 BID Pimasertib 
DL1 
45 BID Pimasertib 
DL2 
60 BID Pimasertib 
 
 [Study Schema] – See Schedule of Assessments   
4.0  
OBJECTIVES 
 
 
4.1 
PRIMARY OBJECTIVE 
 
4.1.1 PHASE I PRIMARY OBJECTIVE 
 Establish safety profile and recommended phase II dose for combining pimasertib with bintrafusp alfa (M7824) 
in patients with brain metastases. 
 
4.1.2 PHASE II PRIMARY OBJECTIVE 
Cycle 1  
RP2D 
Cycle 2  Cycle 3  
Pimasertib at selected dose PO BID for 28 days (continuous dosing) 
BINTRAFUSP ALFA (M7824) 1200 mg (every 2 weeks) 
Cycle 4  
At 8 weeks 
Consider SRS for non-responding lesions 
1 Refractory BMets 
Melanoma 
NSCLC 
Breast 

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•  
Time to intracranial progression (defined as progression of existing  
lesions and development of new 
lesions by modified RECIST 1.1)  
•       Overall survival. 
 
4.2 
SECONDARY OBJECTIVES 
• Intracranial progression 4, 8, 12, 16 weeks and every 8 weeks thereafter.  
• Intracranial objective response rate as measured by RANO-BM, iRANO, and RECIST 1.1. 
• Time to second intracranial progression after Salvage SRS  
• Overall survival rateat 24, 52 and 68 weeks . 
• Frequency of grade 3+ intracranial toxicities at 4, 12, 24, 36, 52, and 68 weeks.Frequency of extracranial 
progression and response rate at 8, 16, 24, every 8 weeks. 
• Frequency of neurocognitive decline 12, 24, 36 weeks (optional).Changes in neurocognitive function and health-
related quality of life. 
• Dose, duration and frequency of steroid use for symptomatic management. 
• Evaluation of safety and tolerability of pimasertib/bintrafusp alfa combination 
 
4.3 
EXPLORATORY OBJECTIVE 
• Identify molecular and/or immunological markers from biospecimens (tissue, blood, and CSF) that are associated 
with treatment response and toxicity. 
• Identify imaging biomarkers of response and toxicity (acute radiation effect/radionecrosis and neurocognitive 
changes) from multiparametric MRI and/or delayed PET that predict treatment response and toxicity.  
• Identify correlative or surrogative relationship between systemic (blood) and imaging markers and treatment 
outcomes. 
 
5.0 
PATIENTS 

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5.1 
INCLUSION CRITERIA 
1.       Age ≥ 18 years old. 
2. 
Life Expectancy > 12 weeks. 
3. 
Subjects must be willing and able to comply with scheduled visits, treatment  
schedule, laboratory testing, and other 
requirements of the study. 
4. 
At least one measurable untreated brain lesion ≥ 0.5 cm and <3.0 cm in the  
longest axis according to modified RECIST 
1.1. 
5. 
Prior SRS with up to 10 lesions treated with at least a 14 day interval is   
            allowed as long as the previous treatment volume does not overlap with the   
current targets. The target could be a previously irradiated lesion with clear evidence of progression. 
 
6. 
Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. 
Subjects must be free of neurologic signs and symptoms related to metastatic   brain lesions and must not have required or 
received systemic corticosteroid therapy in the 10 days prior to beginning protocol therapy. 
8. 
Prior treatment with immunotherapy and targeted therapy allowed as long as it did not include a combination of MEKi + anti-
PD(L)-1 antibody and is >14 days prior to start of protocol therapy. All tumor types will be eligible and included in the dose 
escalation phase. Dose expansions will include 10 patients each from lung, breast, and melanoma. 
9. 
Patients with melanoma must have received prior PD-1 based therapy. 
10. 
Patients with NSCLC must have received prior PD-1 based therapy. 
11. Patients with TNBC and HR+ are included (any number of prior lines of therapy- including IO naïve patients).   
12. For HR+ patients, patients are allowed to receive endocrine therapy (anastrozole, letrozole, exemestane, or fulvestrant). 
Concurrent CDK4/6 inhibitors will not be allowed. 
13. Systematic radiation therapy is allowed (>14 day washout)  
14. Prior platinum-based chemotherapy for NSCLC patients is allowed  
15. Adequate organ function as described below: 
 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1500/µL 
Platelets 
≥100 000/µL 

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Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
Creatinine OR 
Measured or calculated b creatinine clearance 
(GFR can also be used in place of creatinine 
or CrCl) 
≤1.5 × ULN OR 
≥60 mL/min for participant with 
creatinine levels >1.5 × institutional ULN 
Hepatic 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants 
with liver metastases) 
Coagulation 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is 
receiving anticoagulant therapy as long as 
PT or aPTT is within therapeutic range of 
intended use of anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
GFR=glomerular filtration rate; ULN=upper limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood 
cell (pRBC) transfusion within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; 
laboratory value requirements should be adapted according to local regulations and 
guidelines for the administration of specific chemotherapies. 
 

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Women of child-bearing potential (WOCBP) must not be breastfeeding and must have a negative pregnancy test within 3 days prior to 
initiation of dosing. She must agree to use an acceptable method of birth control from the time of the  
negative pregnancy test up to 
120 days after the last dose of study drug. WOCBP must agree to adhere to the contraceptive guidance in Appendix 5.  
 
Note: A female participant is eligible to participate if she is not a woman of childbearing potential as defined in Appendix 5. 
 
Fertile men must agree to use an acceptable method of birth control as described  in Appendix 5 while on study drug and up to 120 
days after the last dose of study drug and also refrain from donating sperm during this period. 
All associated toxicity from previous or concurrent cancer therapy must be  
resolved (to ≤ Grade 1 or Baseline) prior to study treatment administration, unless stable status as assessed by investigator e.g. 
hypothyroidism, adrenal insufficiency, or other.Steroids for physiological replacement are allowed. 
5.2 
EXCLUSION CRITERIA 
1.       Patients with clinical or radiographic evidence of leptomeningeal disease. 
2.       Those who experienced grade 3 or 4 neurotoxicity from prior SRS. 
3. 
Contraindications to MRI (implanted metal device or foreign bodies) or MRI contrast (insufficient renal function or allergy). 
4. 
Subjects with major medical, neurologic or psychiatric condition who are judged as unable to fully comply with study therapy 
or assessments should not be enrolled. 
5. 
Active secondary malignancy unless the malignancy is not expected to interfere with the evaluation of safety and is approved by 
the PI. Examples of the latter include basal or squamous cell carcinoma of the skin, in-situ carcinoma of the cervix, and isolated 
elevation of prostate-specific antigen. Subjects with a completely treated prior malignancy and no evidence of disease for ≥ 2 
years are eligible. 
6. 
Has a known history of or is positive for hepatitis B (hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C 
virus infection (note treated and cured history of hepatitis C is allowed)(hepatitis C virus [HCV] RNA [qualitative] is detected). 
Note: Without known history, testing needs to be performed to determine eligibility. Hepatitis C antibody (Ab) testing is allowed 
for screening purposes. 
7. 
Has a known history of human immunodeficiency virus (HIV) infection. No HIV testing is required unless mandated by local 
health authority. 
8. 
The use of corticosteroids is not allowed for 10 days prior to initiation of therapy (based upon 5 times the expected half-life of 
dexamethasone) except patients who are taking steroids for physiological replacement. If alternative corticosteroid therapy has 
been used, consultation with the PI is required to determine the washout period prior to initiating study treatment. 

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9. 
Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other 
immunosuppressive medications within 14 days of study initiation. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. 
10. 
Major surgical procedure, open biopsy (excluding skin cancer resection), or significant traumatic injury within 14 days of 
initiating study drug (unless the wound has healed) or anticipation of the need for major surgery during the study. 
11. 
Non-healing wound, ulcer, or bone fracture. 
12. 
Women who are breast-feeding or pregnant. 
13. 
Subjects with a history of serious intercurrent chronic or acute illness, such as cardiac or pulmonary disease, hepatic 
disease, bleeding diathesis or recent major bleeding events or other illness considered by the Investigator as high risk for 
investigational drug treatment 
14. 
Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep 
vein thrombosis or pulmonary embolism within the 6 months before start of study medication (except for adequately treated 
catheter-related venous thrombosis occurring more than 1 month before the start of study medication). 
15. 
History of clinically significant cardiac disease or congestive heart failure > New York Heart Association (NYHA) class 2. 
Subjects must not have unstable angina (anginal symptoms at rest) or new-onset angina within the last 3 months or myocardial 
infarction within the past 6 months. 
16. 
Investigational drug use within 14 days (or 5 half-lives, whichever is longer) of the first dose of bintrafusp alfa and/or pimasertib. 
17. 
Has a history of (Grade 3 or 4) non-infectious pneumonitis that required steroids or current pneumonitis. 
18. 
Retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of retinal vein 
occlusion (RVO) or any eye condition that would be considered as risk factor for RVO (e.g. uncontrolled glaucoma or ocular 
hypertension) 
19. 
Creatine phosphokinase level at baseline NCI CTCAE Grade ≥2 (>2.5x ULN – 5x ULN) and/or previous history of myositis or 
rhabdomyolysis 
20. 
For NSCLC cohort patients whose tumor exhibit activating EGFR mutation, ALK         
      or ROS translocation and have a standard of care molecular targeted therapy     
available for these mutations, will be excluded from this study. Patients who   
progressed or could not tolerate these standard of care molecular targeted agents  
are eligible for this study. Lung adenocarcinoma patients may be consented prior  
to the EGFR and ALK status being known, but EGFR and ALK status must be  
determined prior to initiating therapy  
22.         Administration of live, attenuated vaccine therapies for the prevention of infectious  
           diseases within 4 weeks prior to day 1 of treatment and during therapy.  Locally      

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           approved COVID-19 vaccines are allowed. 
6.0 
TRIAL TREATMENT 
 
6.1 
BINTRAFUSP ALFA (M7824)  
Bintrafusp alfa (MBINTRAFUSP ALFA (M7824) drug product is a sterile, liquid formulation formulation presented at a 
concentration of 600 mg/vial in United States Pharmacopeia (USP) type I glass vial closed with a rubber stopper and sealed 
with an aluminum plastic crimping cap. 
Each vial contains 600 mg of Bintrafusp alfa (BINTRAFUSP ALFA (M7824) BINTRAFUSP ALFA (M7824) as a preservative-
free histidine-buffered solution (pH=5.5) containing trehalose dihydrate, sodium chloride, L-methionine and polysorbate 20 
(Tween 20). Only excipients that conform to the current USP are used for BINTRAFUSP ALFA (M7824) drug product. 
Subjects will receive IV infusion of Bintrafusp alfa (BINTRAFUSP ALFA (M7824) BINTRAFUSP ALFA (M7824) over 1 
hour (-10 minutes / +20 minutes) once every 2 weeks as detailed in the Schedules of Assessments. Modifications of the infusion 
rate due to infusion-related reactions are described in Section 6.2.3.  
Bintrafusp Alfa (M7824) will be shipped in transport cool containers (2°C to         8°C) that are monitored with temperature 
control devices. 
 
All IMPs will be packaged and labeled in accordance with  all applicable  regulatory requirements and Good Manufacturing 
Practice Guidelines. 
 
 
6.1.1 DOSAGE AND ADMINISTRATION 
The dose for Bintrafusp Alfa (M7824) is a flat dose of 1200mg. Subjects will receive Bintrafusp Alfa (M7824) once every 2 
weeks.. Subjects who have experienced a persistent, confirmed PR or CR may continue treatment through the end of 12 months, 
although additional treatment is possible. If the Principal Investigator believes that a subject may benefit from treatment beyond 

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12 months, it may be permissible after discussion with the EMD Serono.  If there is no evidence of radiographic or clinical 
progression, then the patient may continue on study at the discretion of the principal investigator. 
Participants who are discontinued due to an AE that are subsequently well managed or resolved after stopping therapy, but prior 
to the end of the study. Prior to reinitiation, the Principal Investigator will need to confirm that the benefit of reinitiating 
treatment outweighs any risk involved, such as that which led to initial treatment discontinuation. For participants with only 
stable disease at the time of discontinuation, the Principal Investigator should confirm that no other reasonable treatment options 
are available.  
In addition, to be eligible for reinitiation (after dose delay), the participant must not have previously withdrawn consent for this 
trial and should have been followed up with regular eCRF documented evaluation scans up to reinitiation of treatment. 
Prior to reinitiation of the study intervention, malignant disease must be radiologically restaged within 28 days of dosing to 
assess all known disease sites. Additionally, relevant safety laboratory assessments, including both full hematology and full 
chemistry results within 2 weeks, must be available and verified. The Principal Investigator will determine whether additional 
evaluation and work up are required on a case-by-case basis. A discussion with the study team is warranted to determine whether 
PK/biomarker testing is indicated upon restarting treatment. 
The participant should reinitiate treatment at the treatment phase visit where they left off according to the Schedule of 
Activities. Participants who reinitiate treatment should stay on study and should be treated and monitored according the 
Schedule of Activities for the rest of the study.   
 
6.2 
PIMASERTIB 
 The drug substance pimasertib (recommended international non-  
 
 
proprietary name [INN]; also known 
as MSC1936369B or AS703026) is a  
 
biaryl amine derivative. Its chemical name according to International  
 
Union of Pure and Applied Chemistry (IUPAC) is N-[(2S)-2,3- 
 
 
 
dihydroxypropyl]-3-[(2-
fluoro 4-iodophenyl) amino] isonicotinamide  
 
 
hydrochloride. 
 Pimasertib is formulated as 15mg and 30mg (as free base) hard gelatin  
 
 
size 
0 
capsules 
for 
oral 
administration. Each of the strengths of pimasertib   
is presented in a different color capsule (see below). 

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1. 
15mg: Green 
2. 
30mg: Gray 
Capsules consist of pimasertib combined with the following inactive ingredients: lactose, microcrystalline cellulose, 
croscarmellose sodium, poloxamer 188, and magnesium stearate. 
Pimasertib drug product is manufactured according to Good Manufacturing Practices (GMP). 
Pimasertib will be provided for clinical use by EMD Serono as capsules packaged in amber glass bottles with high-density 
polyethylene (HDPE) caps, supplied in individual cardboard boxes. 
Each box and drug unit will be numbered to allow complete drug  accountability. 
All drugs will be supplied with Certificates of Analysis.  Packaging and labeling will be in accordance with applicable local 
regulatory requirements and applicable GMP Guidelines. 
 It is stored at room temperature (≤ 25°C/77ºF). 
Please note that drug disposal will be on site according to MDACC Institutional policy.   
 
6.2.1 DOSAGE AND ADMINISTRATION 
Pimasertib will be administered orally at a dose of either 30 mg, 45 mg, or 60 mg twice daily (BID) continuously, based on 
RP2D. Starting dose level for phase 1 is 45mg orally BID. 
Pimasertib can be taken in fasted state or after a light meal. The subject will be              instructed to swallow the capsules without 
biting into breaking or opening them, or attempting to dissolve the content in water prior to taking them. 
 
 
 
A time window of 12 ± 3 hours between the administration of the morning and evening dose of pimasertib is considered 
acceptable.   

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Table 1: Trial Treatments and Description 
Product 
Dose 
Dose 
Frequency 
Route of 
Administration 
Appearance 
Storage 
Conditions 
(per label) 
BINTRAFUSP 
ALFA 
(M7824) 
 1200 
mg 
Every 2 
Weeks 
IV Infusion 
 
2oC – 8oC 
Pimasertib 
60mgA 
Twice Daily 
Oral 
 
 
A=DEPENDING ON THE PHASE OF THE STUDY THE PARTICIPANT IS PARTICIPATING IN, THEY COULD RECEIVE 30-60MG OF THE DRUG.   
 
6.2.3 DOSE MODIFICATION 
 
Infusion-Related Reactions 
 
IRRs are defined as any signs or symptoms experienced by participants  
 
 
during the infusion of pharmacologic 
or biologic agents or any event   
 
occurring during or within 1 day of drug administration. IRRs are common  
 
ADRs with monoclonal antibodies timely related to drug administration   
 
and 
have 
been 
reported 
as 
anaphylaxis, anaphylactoid reactions, and  
 
 
cytokine release syndrome, among other terms used. IRRs are 
 
 
risks (adverse reactions) for Bintrafusp Alfa (M7824), and the                                precautions and management are 
provided in Table 6. 
A. Signs and symptoms of infusion related reactions (IRRs) including hypersensitivity include but not limited to pyrexia, chills, 
flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria, were reclassified as risks (adverse reactions). 
 
B. Management--Patients who experience infusion-associated symptoms may be treated symptomatically with acetaminophen, 
ibuprofen, diphenhydramine, and/or cimetidine or another H2 receptor antagonist, as per standard practice. Serious 

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infusion-associated events manifested by dyspnea, hypotension, wheezing, bronchospasm, tachycardia, reduced oxygen 
saturation, or respiratory distress should be managed with supportive therapies as clinically indicated. 
 
 
 
 
 
 
Immune-Mediated Pneumonitis 
 
Lung Toxicities 
Pneumonitis 
Deﬁnition: Focal or diffuse inﬂammation of the lung parenchyma (typically identiﬁed on CT imaging) 
No symptomatic, pathologic, or radiographic features are pathognomonic for pneumonitis 
Diagnostic work-up 
Should include the following: CXR, CT, pulse oximetry 
For G2 or higher, may include the following infectious work-up: nasal swab, sputum culture and 
sensitivity, blood culture and sensitivity, urine culture and sensitivity 
Grading 
Management 
G1: Asymptomatic, conﬁned to one lobe of the 
lung or < 25% of lung parenchyma, clinical or 
diagnostic observations only 
Continue Immune Checkpoint inhibitor (ICPi)  
If clinically indicated. Monitor participants 
weekly or more frequently as needed with 
history, physical examination and pulse 
oximetry; may also offer CXR. May offer one 
repeat CT scan in 3 to 4 weeks; in patients who 
have had baseline testing, may offer a repeat 
spirometry/DLCO in 3 to 4 weeks  

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Lung Toxicities 
If symptoms appear and/or changes in the 
physical exam are noted, treat as G2 
G2: Symptomatic, involves more than one lobe of 
the lung or 25%-50% of lung parenchyma, 
medical intervention indicated, limiting 
instrumental ADL 
Hold ICPi until resolution to G1 or less 
Prednisone 1 to 2 mg/kg/d and taper by 5 to 10 
mg/wk. over 4 to 6 weeks Consider bronchoscopy 
with BAL 
Consider empirical antibiotics 
Monitor every 3 days with history and physical 
examination and pulse oximetry, consider CXR; 
no clinical improvement after 48 to 72 hours of 
prednisone, treat as G3 
G3: Severe symptoms, hospitalization required, 
involves all lung lobes or 50% of lung 
parenchyma, limiting self-care 
ADL, oxygen indicated 
G4: Life-threatening respiratory compromise, 
urgent intervention indicated (intubation) 
Permanently discontinue ICPi 
Empirical antibiotics; (methyl)prednisolone IV 1-
2 mg/kg/d; no improvement after 48 hours, may 
add inﬂiximab 5 mg/kg or mycophenolate mofetil 
IV 1 g twice a day or IVIG for 5 days or 
cyclophosphamide; taper corticosteroids over 4-6 
weeks 
Pulmonary and infectious disease consults if 
necessary 
Bronchoscopy with BAL ± transbronchial biopsy 
Patients should be hospitalized for further 
management 
Additional considerations 
GI and Pneumocystis prophylaxis with PPI and Bactrim may be offered to patients on prolonged 
corticosteroid use (> 12 weeks), according to institutional guidelines 
Consider calcium and vitamin D supplementation with prolonged corticosteroid use 
The role of prophylactic ﬂuconazole with prolonged corticosteroid use (> 12 weeks) remains unclear, 
and physicians should proceed according to institutional guidelines 
Bronchoscopy + biopsy; if clinical picture is consistent with pneumonitis, no need for biopsy 

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Lung Toxicities 
All recommendations are expert consensus based, with beneﬁts outweighing harms, and strength of 
recommendations are moderate. 
 
Table 2: Treatment Modification for Symptoms of Infusion-related Reactions Caused by BINTRAFUSP ALFA (M7824) 
NCI-CTCAE Grade 
Treatment Modification for Bintrafusp 
Alfa (M7824) 
Grade 1 – mild 
• Mild reaction; infusion interruption 
not indicated intervention not 
indicated. 
• Decrease the Bintrafusp Alfa 
(M7824) infusion rate by 50% and 
monitor closely for any worsening. 
• The 
total 
infusion 
time 
for 
Bintrafusp Alfa (M7824) should 
not exceed 120 minutes 
Grade 2 – moderate 
• Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic 
treatment 
(for 
example, antihistamines, NSAIDs, 
narcotics, IV fluids); prophylactic 
medications indicated for ≤ 24 
hours. 
• Stop Bintrafusp Alfa (M7824) 
infusion. 
• Resume infusion at 50% of 
previous rate once infusion-related 
reaction has resolved or decreased 
to at least Grade 1 in severity, and 
monitor closely for any worsening 
Grade 3 or Grade 4 – severe or life-
threatening 
• Grade 3: Prolonged (for example, 
not 
rapidly 
responsive 
to 
• Stop the Bintrafusp Alfa (M7824) 
infusion 
immediately 
and 
disconnect infusion tubing from 
the subject.  

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symptomatic medication and / or 
brief interruption of infusion); 
recurrence of symptoms following 
initial 
improvement; 
hospitalization 
indicated 
for 
clinical sequelae. 
• Grade 
4: 
Life-threatening 
consequences; urgent intervention 
indicated. 
• Subjects have to be withdrawn 
immediately form Bintrafusp Alfa 
(M7824) treatment and must not 
receive any further Bintrafusp Alfa 
(M7824) treatment 
IV = intravenous; NCI-CTCAE = National Cancer Institute – Common Terminology Criteria for Adverse Event; NSAIDs = nonsteroidal 
anti-inflammatory drugs 
Additional Modifications for Subjects with Grade 2 Infusion-related Reactions 
If, in the event of a Grade 2 infusion-related reaction that does not improve or worsens after implementation of the modifications 
indicated in Table 2 (including reducing the infusion rate by 50%), the Principal Investigator may consider treatment with corticosteroids 
and the infusion of BINTRAFUSP ALFA should be stopped for that day. At the next infusion, the Principal Investigator may consider 
the addition of H2-blocker antihistamines (for example, famotidine or ranitidine), in addition to premedication, for select subjects. 
However, prophylactic steroids are NOT permitted. If the subject has a second infusion-related reaction Grade ≥ 2 on the slower infusion 
rate, with or without the addition of further medication to premedication, the infusion should be stopped and the investigator may 
consider withdrawal of this participant from the study. 
Immune-Related Adverse Events 
For reporting irAE severity/toxicity grading, refer to CTCAE v.5 toxicity grading system. 
For treatment management of irAE per CTCAE v.5 criteria, refer to American Society of Clinical Oncology (ASCO) Clinical Practice 
Guidelines and National Comprehensive Cancer Network irAE Management Guidelines. Refer to Appendix 6 and 7.   
The recommendations for irAE management, in accordance with the joint American Society of Clinical Oncology Clinical Practice 
Guidelines (Brahmer, 2018) and National Comprehensive Cancer Network (NCCN Guidelines®), are listed in Appendix 6.  

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Treatment of irAEs is mainly dependent upon severity as defined by NCI-CTCAE v5.0. In general, management by CTCAE v5.0 grading, 
as per ASCO, is listed below: 
• Grade 1: study treatment should be continued with close monitoring, with the exception of some neurologic, hematologic, and cardiac 
toxicities.  
• Grade 2: study treatment may be suspended for most Grade 2 toxicities, with consideration of resuming when symptoms revert to 
Grade 1 or less. Corticosteroids may be administered (initial dose of 0.5 to 1 mg/kg/day of prednisone or equivalent).  
• Grade 3: study treatment is generally suspended and the high-dose corticosteroids (prednisone 1 to 2 mg/kg/day or 
methylprednisolone 1 to 2 mg/kg/day) treatment should be initiated. Corticosteroids should be tapered over the course of at least 4 
to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy.  
• Grade 4: in general, permanent discontinuation of study treatment is recommended, with the exception of endocrinopathies that have 
been controlled by hormone replacement. 
For organ/system specific management guidelines, review ASCO guideline tables in Appendix 7. 
Since inhibition of PD-L1 stimulates the immune system, irAEs may occur. Treatment of irAEs is mainly dependent upon severity (NCI-
CTCAE grade): 
• Grade 1 to 2: treat symptomatically or with moderate dose steroids, more frequent monitoring 
• Grade 1 to 2 (persistent): manage similar to high grade AE (Grade 3 to 4) 
• Grade 3 to 4: treat with high dose corticosteroids 
Anemia 
Anemia is considered a important identified risk based on toxicological findings with Bintrafusp Alfa (M7824) in cynomolgus monkey 
indicating a decrease in Hgb, RBCs, and hematocrit that was fully reversible or showed a substantial trend toward recovery. Notably, 
there are many reasons for anemia in patients with advanced cancer, which is why a thorough investigation of new anemia cases of 
unspecified etiology is requested.  
 Risk management measures in addition to routine laboratory tests will include: 

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• Subjects must enter the study with Hgb values at least 9 g/dL, independent of recent (≤ 14 days) packed red blood cell transfusion 
and/or use of an erythropoietin-stimulating agent.  
• Routine monitoring of Hgb will be performed every 2 weeks (prior to treatment).Instructions for study treatment 
discontinuation or modification in case of anemia will be provided, briefly described here: In case of any Hgb < 8 g/dL, the 
Principal Investigator should use discretion to initiate anemia work up, including Coombs, haptoglobin, indirect bilirubin and 
peripheral smear, and prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio 
(INR); Hgb and hematocrit are to be closely monitored. 
• For new anemia events assessed as treatment-related, items queried may include but are not limited to detailed relevant past 
medical and treatment history, bruising tendency, history of blood transfusions and/or dependency, and a request for an updated 
eCRF including details such as concomitant medications, all laboratory data, updated dosing information and recent tumor 
evaluation scans. 
If a subject experiences significant anemia, then the amount of blood to be drawn may be reduced by not taking blood at selected 
time points for PD-L1 target occupancy, immunomonitoring, soluble factors, and TGFβ. The decision to reduce the time points 
for these biomarkers will be taken by the Principal Investigator. 
• Evaluation Guidance of  baseline anemia and Suspected Treatment-related Anemia AEs 
Baseline anemia evaluation (prior to transfusion, if feasible) 
Hemoglobin and CBC with differential (e.g. MCV, RDW, ANC, hematocrit, reticulocytes 
counts) 
Peripheral blood smear for cell morphological assessment 
Complete metabolic panel including liver panel-LFTs, bilirubin, LDH, renal function, and 
serum folate, B12 values and other chemistries 
Coagulation factors (PT, PTT, INR) 
Urinalysis including culture 
Iron panel (TIBC, ferritin, Fe) 

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TSH/hormonal panel 
Fecal-occult blood testing 
haptoglobin 
Further recommendation based on suspected etiology (in addition to baseline anemia 
testing) 
Unknown etiology, 
suspect possible 
hemolysis 
Coombs test, fibrinogen, d-dimer 
Consider hematology consultation. 
Consider blood transfusion at clinical discretion. 
Unknown etiology, 
suspect possible 
bleeding 
Consider blood transfusion at clinical discretion. 
Consider surgical/interventional radiology consultation. 
Consider imaging, as clinically indicated (e.g. FAST scan, CT 
scan, MRI, angiography). 
Consider endoscopy (upper/lower)  
Unknown etiology 
despite above work-up 
Hematology consultation 
Consider bone marrow aspiration/morphologic evaluation 
 
Rash with Hyperkeratosis / Keratoacanthoma / Squamous Cell Carcinoma of the Skin 
Treatment-related skin lesions with hyperkeratosis, keratoacanthoma, cutaneous squamous cell carcinoma possibly due to TGFβ 
inhibition are important identified risks (adverse reactions) for Bintrafusp Alfa (M7824). They have been manageable and did not lead 
to permanent discontinuations in Bintrafusp Alfa (M7824) studies. Patients with known Lynch Syndrome who develop 

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keratoacanthomas on study are encouraged to be evaluated for Muir Torre syndrome.  Monitoring will include skin assessments as 
defined in the Schedules of Assessments (Section 8.0), with biopsy of suspicious lesions. Management should be discussed with the 
Principal Investigator on a case-by-case basis. Dermatological consults should be requested as needed in the event that possible drug-
related skin toxicity is suspected by the investigator. 
Impaired Wound Healing 
Due to the involvement of TGFβ in repair of skin and other tissue injuries, impaired wound healing is considered an important potential 
risk. For any surgeries conducted post-treatment initiation, surgical wound healing will be closely monitored. Management should be 
discussed with the Principal Investigator on a case-by-case basis. Dermatological consults should be requested as needed. 
Bleeding Adverse Events 
Bleeding Adverse Events 
• 
Bleeding adverse events are considered important identified risk for bintrafusp alfa. 
• 
In general, mild and moderate mucosal bleedings resolve without discontinuation of treatment. 
• 
These events may include, but are not limited to the following: 
o 
Epistaxis 
o 
Hemoptysis  
o 
Gingival bleeding 
o 
Hematuria 
Non-tumor Bleeding 
Grading 
Management 
Grade 2 
• 
If resolves to Grade ≤ 1 by the day before the 
next infusion, study intervention may be 
continued 
• 
If not resolved to Grade ≤ 1 by the day before the 
next infusion, but is manageable and /or not 
clinically relevant, consult Medical Monitor to 
assess if clinically reasonable to administer the 
following infusion. 
Grade 3 
 
• 
Permanently discontinue treatment unless an 
alternative explanation can be identified (such as 
concomitant use of antithrombotic agents, 
traumatic events, etc.)  

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• 
In case of alternative explanations, hold study 
treatment until the event recovers to Grade ≤ 1 
Grade 4 
• 
Treatment must be permanently discontinued if 
no alternative explanation is identified. 
Tumor Bleeding 
Grade ≥ 2 
• 
Study treatment must be held till the event 
recovers to Grade ≤ 1 
• 
Permanently discontinue treatment if the 
Investigator considers the participant to be at risk 
for additional severe bleeding. 
 
Ocular toxicity 
If a subject experiences Retinal Vein Occlusion the pimasertib treatment must be immediately stopped. Appropriate follow-up and 
treatment measures must be taken by the treating ophthalmologists.  
If a subject shows a symptomatic serous retinal detachement: Withhold treatment for ≤3 weeks, if improved to grade 0/1, resume at 
same dose level. If not improved, resume at the lower dose level or permanently discontinue pimasertib treatment. Management should 
be discussed with Principal Investigator and ophthalmologist. 
Elevation of Serum Creatine Phosphokinase 
Subjects should be advised to immediately report any muscle pain, tenderness or weakness, or any macroscopic myoglobinuria (tea-
colored urine). Subject-reported muscle symptoms or urine discoloration should be investigated with CPK measurements and urinalysis 
for myoglobinuria.  
CPK measurement should be at screening and every 4 weeks; at any time for symptomatic patients.  Assess with differentiation if 
irAE or due to Pimasertib; including DD presence/absence of further symptomatic findings: full history (including conmeds), 
exercises, training, muscular injury, muscular injections, CPK isoenzymes, and etc.   
 

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CPK increase G4: Withhold pimasertib treatment for ≤3 week 
Any CPK elevation and myalgia: If improved to grade ≤3, resume at lower dose level, if not improved within 3 weeks, permanently 
discontinue pimasertib treatment. 
Dehydration 
Dehydration and renal failure secondary to GI toxicity have been reported in clinical trials with pimasertib. Therefore, subjects should 
be advised to maintain adequate hydration at all times. Any subject with mucositis or other GI or other conditions likely to result in 
dehydration must be closely monitored for signs of dehydration. Should adequate hydration not be achievable because of severe GI 
symptoms or mucositis, for example, subjects should return to the investigational site or seek other medical care to avoid renal 
impairment and renal failure. 
Dose Interruptions for Adverse Events not related to Study Drug 
In case of Grade 3 and Grade 4 AEs not study drug-related, the study treatment may be interrupted based on the Principal Investigator 
assessment and the subject will be medically treated for the event. 
If the AE reduces to a lower tolerable grade the study treatment might be resumed in the subsequent cycle. If the AE remains the same 
in spite of medical treatment until the next treatment (second cycle after the AE occurred) a discussion with the Principal Investigator 
should occur and consideration of a possible extension of the dose interruption for up to 1 additional cycle or a permanent withdrawal 
from the study treatment should be considered. 
If upon the resumed study treatment the subject experiences the same AE this should be re-discussed with the Principal Investigator to 
assess permanent withdrawal from the study treatment. 
Grade 3 and 4 laboratory abnormalities that do not have clinical significance do not require dose interruption. 
 
 
6.2.4 SRT AND DOSE INTERRUPTIONS 

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Patients that have to hold systemic therapy to receive SRT are allowed to resume therapy within 6 weeks of holding therapy if 
they meet treatment safety parameters. 
 
6.2.5 RESUMPTION OF TREATMENT AFTER DOSE DELAY 
 
Patients may resume therapy at the same doses after dose interruption as long as they continue to meet the treatment safety 
parameters. 
 
6.2.6 CONCOMITANT AND EXCLUDED THERAPIES 
Steroids are allowed to manage AEs as described in protocol. Medications or vaccinations specifically prohibited in the exclusion criteria 
(See  section 5.2) are not allowed during the ongoing trial. The following are also prohibited and are not allowed: 
• 
Any traditional Chinese medication used as anticancer treatment (regardless of the type of cancer) is prohibited. Traditional 
Chinese medication for indications other than anticancer treatment, such as supportive care, may be administered at the discretion of the 
Investigator.  
• 
Herbal remedies with immunostimulating properties (e.g., mistletoe extract) or known to potentially interfere with major organ 
function (e.g., hypericin). 
If there is a clinical indication for any medication or vaccination specifically prohibited during the trial, discontinuation from trial therapy 
or vaccination may be required. The final decision on any supportive therapy or vaccination rests with the principal investigator and/or 
the subject's primary physician. However, the decision to continue the subject on trial therapy or vaccination schedule requires the 
mutual agreement of the principal investigator, and the subject. 
 
6.2.7 ACCEPTABLE CONCOMITANT MEDICATIONS 
All treatments that the Principal Investigator considers necessary for a subject’s welfare may be administered at the discretion of the 
Principal Investigator in keeping with the community standards of medical care. All concomitant medication will be recorded on the 
eCRF including all prescription, over-the-counter (OTC) products, herbal supplements, and IV medications and fluids. If changes occur 
during the trial period, documentation of drug dosage, frequency, route, and date should also be included on the eCRF. 

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All concomitant medications received within 28 days prior to the screening visit  and up to 30 days after the last dose of trial treatment 
should be recorded.  Concomitant medications administered 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs. 
 
6.2.8 PERMITTED THERAPIES: SRT 
For patients that are deriving clinical benefit from protocol treatment, but having evidence of progression in brain lesions that are 
amenable to SRS, treatment with SRS is allowed and patients can remain on systemic therapy. Patients will be censored for brain 
metastasis response unless one measurable lesion remains unirradiated. Patients will continue to be monitored for intracranial PFS.  
 
6.2.9 PERMITTED THERAPY FOR BRAIN EDEMA 
 
 
Patients that develop neurologic symptoms suspected to be secondary to brain edema are allowed to receive steroids as 
clinically indicated. 
 
6.2.10  PERMITTED THERAPY: BRAIN SURGERY 
 
 
Patients that develop an indication for brain surgery will be managed as clinically indicated. They will be assessed 
post-operatively in the setting of the MD Anderson Brain Metastasis Clinic (or similar multi-disciplinary setting) to determine whether 
resuming systemic therapy on protocol is warranted. The same dose interruptions and treatment resumption criteria that apply to SRT 
will apply to neurosurgical interevention as well. 
7.0 
PROHIBITED CONCOMITANT MEDICATIONS 
As stated for the exclusion criteria in Section 5.2, subjects must not have had chemotherapy, radiotherapy (other than palliative 
radiotherapy delivered in a normal organ-spearing technique), major surgery, or received another investigational agent within 14 days 
before the start of trial treatment. 
The following treatments must not be administered during the trial: 

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• Immunotherapy including interferon, immunosuppressive drugs (for example, chemotherapy or systemic corticosteroids except 
for short term treatment of allergic reactions, endocrine replacement therapy at low dose prednisone [≤ 10 mg daily] or 
equivalent, or for the treatment of irAEs or other appropriate short term steroid use), or other experimental pharmaceutical 
products. Short term administration of systemic steroid or other immunosuppressant such as infliximab or mycophenolate (that 
is, for allergic reactions or the management of irAEs) is allowed. Steroids with no or minimal systemic effect (topical, inhalation) 
are allowed.  
• Adefovir. 
• Prophylactic use of corticosteroids for infusion related reactions is prohibited. 
• Any live vaccine therapies for the prevention of infectious disease. Administration of inactivated vaccines is allowed (for 
example, inactivated influenza vaccines or approved SARS-COV-2 vaccines). 
• Vaccines will be allowed and will require one week between administration and treatment.   
If the administration of a non-permitted concomitant drug becomes necessary during the trial, the subject will be withdrawn from trial 
treatment (the Principal Investigator may be contacted to discuss whether the BINTRAFUSP ALFA must be discontinued). 
Medications other than those specifically excluded in this trial (as outlined in this section) may be administered for the management of 
symptoms associated with the administration of Bintrafusp Alfa (M7824) as required. These might include analgesics, anti-emetics, 
antihistamines, diuretics, anti-anxiety medications, and medication for pain management, including narcotic agents. 
Any additional concomitant therapy that becomes necessary during the trial and any change to concomitant drugs must be recorded in 
the corresponding section of the eCRF (Prometheus) and medical record, noting the name, dose, duration, and indication of each drug. 
The following non-drug therapies must not be administered during the trial (and within 28 days before the start of trial treatment): 
• Major surgery (excluding prior diagnostic biopsy).Herbal remedies with immunostimulating properties (for example, mistletoe 
extract) or known to potentially interfere with major organ function (for example, hypericin) 
• Subjects should not abuse alcohol or other illicit drugs during the trial 
Drugs known to prolong the QT interval must be used with caution if they cannot be avoided. The list of the drugs in question is given 
at the following web address: http://crediblemeds.org/everyone/composite-list-all-qtdrugs/?rf=All 

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Furthermore, caution should be exercised when starting or increasing the dose of any medication that is considered to be associated with 
muscle toxicity (e.g., 3-Hydroxy-3-Methylglutaryl- Coenzyme A [HMG CoA] reductase inhibitors [statins]). 
Interactions 
• Pimasertib is a substrate of Cytochrome P450 (CYP) Isoforms CYP3A4 and CYP2C19, and may possibly inhibit CYP2C9. 
Based on this, it was concluded that concomitant administration with the following drugs should be used with caution or avoided if 
possible: 
• Strong inhibitors of CYP3A4 
• Strong inducers of CYP3A4 
• Strong inhibitors of CYP2C19 
• Substrates of CYP2C9 with a narrow therapeutic index 
A list of drugs that should be used with caution or avoided is presented can be found here: 
https://drug-interactions.medicine.iu.edu/Main-Table.aspx 
SPECIAL PRECAUTIONS 
As a routine precaution, subjects all enrolled in this trial must be observed for 2 hours in the CTRC post end of infusion, in an area with 
resuscitation equipment and emergency agents at least for the first two doses of treatment with Bintrafusp Alfa (M7824). If no medical 
problems arise during the first two treatments, then the 2 hour observation period does not need to continue starting with the third dose 
of treatment. At all times during Bintrafusp Alfa (M7824) treatment, immediate emergency treatment of an infusion-related reaction or 
a severe hypersensitivity reaction according to institutional standards must be assured. In order to treat possible anaphylactic reactions, 
for instance, dexamethasone 10 mg and epinephrine in a 1:1000 dilution or equivalents should always be available along with equipment 
for assisted ventilation. 

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Infusion of Bintrafusp Alfa (M7824) will be stopped in case of Grade ≥ 2 hypersensitivity, inflammatory response, or anaphylactic 
reaction. The treatment recommendations for infusion-related reactions and severe hypersensitivity reactions according to the NCI are 
outlined in Section 6.2.3. 
Principal Investigators should also monitor subjects closely for potential irAEs (described in Section 6.2.3), which may become 
manifest after several weeks of treatment. Such events may consist of persistent rash, diarrhea and colitis, autoimmune hepatitis, 
arthritis, glomerulonephritis, cardiomyopathy, or uveitis and other inflammatory eye conditions. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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8.0 
SCHEDULE OF ASSESSMENTS 
TABLE 3 SCHEDULE OF ASSESSMENTS 
Trial Period: 
Screening Phase 
 
 
Treatment Cycles a 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening  
 
C1
D1 
 
C2 
D1 
 
3 
4 
To be 
repeated 
beyond 8 
cycles 
Discontinuati
on 
Safety  
Follow-
up 
Follow 
Up  
Visits b 
Survival 
Follow-
Upp 
C1 
D15 
C2 
D15 
5 6 7 8 
Scheduling Window (Days): 
-28 to -1 
 
 
 
± 
3 
 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
At time of 
Discontinuati
on 
30 days 
post 
discontin
uation 
± 7 
Every 6 
weeks 
post 
discontinu
ation 
± 7 
Every 12 
weeks 
± 7  
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
  
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical 
History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medication Review 
X 
X 
X 
X 
X 
X X X X X X
X 
 
 
 
Trial Treatment 
Administration c 
 
X 
X 
X 
X 
X X X X X X
 
 
 
 

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Trial Period: 
Screening Phase 
 
 
Treatment Cycles a 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening  
 
C1
D1 
 
C2 
D1 
 
3 
4 
To be 
repeated 
beyond 8 
cycles 
Discontinuati
on 
Safety  
Follow-
up 
Follow 
Up  
Visits b 
Survival 
Follow-
Upp 
C1 
D15 
C2 
D15 
5 6 7 8 
Scheduling Window (Days): 
-28 to -1 
 
 
 
± 
3 
 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
At time of 
Discontinuati
on 
30 days 
post 
discontin
uation 
± 7 
Every 6 
weeks 
post 
discontinu
ation 
± 7 
Every 12 
weeks 
± 7  
Post-study anticancer therapy 
status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
X 
X X X X X X
X 
X 
X 
X 
Physical Examination 
X 
X 
X 
X 
X 
X X X X X X
X 
 
X 
 
Vital Signs, Weight, and 
Heightn 
X 
X 
X 
X 
X 
X X X X X X
X 
 
X 
 
Electrocardiogram (12-Lead 
ECGs)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECHO/MUGA 
X 
 
 
X 
 
 
X  X  X
X 
 
 
 
Ophthalmological Examl 
X 
 
 
 
 
 
X  
 
X  
X 
 
 
 

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Trial Period: 
Screening Phase 
 
 
Treatment Cycles a 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening  
 
C1
D1 
 
C2 
D1 
 
3 
4 
To be 
repeated 
beyond 8 
cycles 
Discontinuati
on 
Safety  
Follow-
up 
Follow 
Up  
Visits b 
Survival 
Follow-
Upp 
C1 
D15 
C2 
D15 
5 6 7 8 
Scheduling Window (Days): 
-28 to -1 
 
 
 
± 
3 
 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
At time of 
Discontinuati
on 
30 days 
post 
discontin
uation 
± 7 
Every 6 
weeks 
post 
discontinu
ation 
± 7 
Every 12 
weeks 
± 7  
ECOG Performance Status 
X 
X 
X 
X 
X 
X X X X X X
X  
 
X 
X 
Neuro-function (NANO) 
X 
X 
 
X 
 
X X X X X X
X 
 
 
 
Neuropsych Testingo/ 
Neurocognitive Testing 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or 
Serum -HCG d 
X 
 
 
X 
 
X X X X X X
X 
 
 
 
Coagulation e 
X 
 
 
 
 
 
 
 
 
  
 
 
 
 
CBC with Differentialk 
X 
X 
X 
X 
X 
X X X X X X
X 
 
X 
 
CMPm 
X 
X 
X 
X 
X 
X X X X X X
X 
 
X 
 
Urinalysis 
X 
 
 
X 
 
X X X X X X
X 
 
 
 

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Trial Period: 
Screening Phase 
 
 
Treatment Cycles a 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening  
 
C1
D1 
 
C2 
D1 
 
3 
4 
To be 
repeated 
beyond 8 
cycles 
Discontinuati
on 
Safety  
Follow-
up 
Follow 
Up  
Visits b 
Survival 
Follow-
Upp 
C1 
D15 
C2 
D15 
5 6 7 8 
Scheduling Window (Days): 
-28 to -1 
 
 
 
± 
3 
 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
At time of 
Discontinuati
on 
30 days 
post 
discontin
uation 
± 7 
Every 6 
weeks 
post 
discontinu
ation 
± 7 
Every 12 
weeks 
± 7  
Lactate dehydrogenase 
(LDH) 
X 
 
 
X 
 
X X X X X X
X 
 
 
 
T3, FT4 and TSH 
X 
X 
 
 
 
X 
 X  
X  
X 
 
 
 
Creatinine Phosphokinase  
X 
X 
 
X 
 
X X X X X X
X 
 
 
 
HIV, HBV, HCV Testing  
X 
 
 
 
 
 
 
 
 
  
 
 
 
 
Efficacy Measurement 
Tumor Imaging & 
Assessment of disease: MRIf  
X 
 
 
 
X 
 
X X 
X 
 
X 
 
X 
 
 
 
Tumor Imaging & 
Assessment of disease: CT’sf 
X 
 
 
 
 
X 
 
 
X  
 
X  
 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 

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Trial Period: 
Screening Phase 
 
 
Treatment Cycles a 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening  
 
C1
D1 
 
C2 
D1 
 
3 
4 
To be 
repeated 
beyond 8 
cycles 
Discontinuati
on 
Safety  
Follow-
up 
Follow 
Up  
Visits b 
Survival 
Follow-
Upp 
C1 
D15 
C2 
D15 
5 6 7 8 
Scheduling Window (Days): 
-28 to -1 
 
 
 
± 
3 
 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
At time of 
Discontinuati
on 
30 days 
post 
discontin
uation 
± 7 
Every 6 
weeks 
post 
discontinu
ation 
± 7 
Every 12 
weeks 
± 7  
Archival Tissue g 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serial Biopsy h 
X 
 
 
x 
 
 
 X  
 
 
 
 
 
 
Blood/Tissue Collection 
X 
 
 
X 
 
X X X X X X
 
 
 
 
Correlative Studies j 
X 
 
 
X 
 
 
 X  
 
 
X 
 
 
 
PK and ADA 
 
X 
 
X 
 
X 
 
 X  
 
X 
X 
 
 
CSFi (optional) 
X 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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a  
Cycles are 4 weeks (28 days) in duration 
b  
Patients who discontinue trial treatment for reasons other than disease progression will move into the Follow-Up phase. Patients 
will be seen every 6 weeks for the first year, then every 12 weeks thereafter up to 2 years. 
c   
M7824 1200 mg every 2 weeks. Pimasertib will be administered at 60mg twice daily.  (30 to 60 mg depending on phase) 
d  
See Page 78 if a woman of child-bearing potential becomes pregnant while on study. Negative pregnancy test within 3 days prior 
to initiation of dosing and continuation of birth control for 120 days after last dose of drug.   
e  
Prothrombin time/International Normalized Ratio, Activated Partial thromboplastin time. 
f  
MRI Scan will be performed every 4 weeks for the first 16 weeks, then every 8 weeks until progression or discontinuation of 
study treatment, whichever comes later. Imaging window is ± 7 days. If scans performed within 4 weeks of discontinuation, 
repeat scans are not required.   
 
CT-CAP or PET-CT will be performed every 8 weeks until progression of discontinuation of study treatment, whichever comes 
later. Imaging window is ± 7 days. If scans performed within 4 weeks of discontinuation, repeat scans are not required.   
 
Please note that if an MRI, CT chest/abdomen/pelvis or PET-CT is not already performed as standard of care per Schedule of 
Assessments in Section 8.1.4, the investigator may choose to perform either or both procedures for assessing progress of the 
patient. 
g  
Obtain archival only if tissue is post PD-1 exposure for melanoma and lung cancer patients. See Section 8.7.1 for additional 
details.  
h  
Patients with biopsiable extracranial disease may have tissue collected. See Section 8.8.   
i  
Cerebrospinal Fluid may be obtained if testing for LMD. See section 8.7.3 for additional details. 
j  
See Section 8.7.   
k  
CBC & CMP is done every 2 weeks (+/- 7 days) prior to infusion.   
l   
Patients will have ophthalmological evaluation at baseline and every 12 weeks. See section 8.3. 
while receiving protocol therapy  
m  
Serum chemistry includes the tests listed (glucose, BUN, creatinine, sodium, potassium, magnesium, chloride, bicarbcionate, 
calcium, phosphorus, total and direct bilirubin, ALT, AST, ALP, LDH, total protein, albumin, CPK, and uric acid). CMP is done 
every 2 weeks prior to infusion. 
n  
Height only taken at Screening 
o  
There will also be a Neurocognitive exam at the 3-month mark 
p  
A follow up call will be done at 90 days to assess patient safety.  

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8.1 
PHYSICAL EXAMINATION 
 
 
8.1.1 FULL PHYSICAL EXAM 
The Principal Investigator or qualified designee will perform a complete physical exam during the Screening period. 
Clinically significant abnormal findings should be recorded as medical history. The time points for  physical exams are 
described in Table 3.0. After the first dose of trial treatment, new clinically significant abnormal findings should be 
recorded as AEs. 
 
 
8.1.2 DIRECTED PHYSICAL EXAM 
The Principal Investigator or qualified designee will perform a directed physical exam as clinically indicated prior to 
the administration of the trial treatment. New clinically significant abnormal findings should be recorded as AEs. 
 
8.1.3 VITAL SIGNS 
Vital signs include temperature, pulse, respiratory rate, weight and blood  pressure. The Principal Investigator or qualified 
designee will take vital signs at   
screening, prior to the administration of each dose of trial treatment and   
during 
the follow-up period as specified in the Trial Flow Chart (Section 8.0). Height will be measured at Screening. 
 
8.1.4 RESPONSE ASSESSMENT 
                        MRI of the brain will be the primary radiological method of disease assessment using modified RECIST 1.1. Treatment 
decisions will be made according to modified RECIST 1.1 while other measurement criteria will be utilized as 
secondary endpoints including  iRANO criteria (See Appendix 1).Quantitative imaging changes on multiparametric 
MRI will be captured to determine early biomarkers of immune response. Standard of care brain MRI with intravenous 
gadolinium contrast and contrast enhanced CT chest/abdomen/pelvis or PET-CT, as clinically indicated, will be used to 
assess both intracranial and extracranial disease at Screening and every 4 weeks for the first 12 weeks, then every 8 
weeks for the first year, then every 12 weeks until progression or discontinuation of study treatment, whichever comes 
 

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later. Imaging window is ± 7 days. If scans performed within 4 weeks of discontinuation, repeat scans are not required.  
Screening MRI and CT assessments must occur within 28 days prior to day 1. 
                        If an MRI, CT chest/abdomen/pelvis or PET-CT is not already performed as standard of care per Schedule of 
Assessments in Section 8.0, the principal investigator may choose to perform either or both procedures for assessing 
the progress of the patient. 
8.2 BIOPSY AND ARCHIVAL TUMOR TISSUE SAMPLE 
 
8.2.1 ARCHIVAL TUMOR TISSUE SAMPLE 
 
 
Archival tumor tissue samples obtained outside of this study for       
                        other purposes will be collected, if available, from all patients. All  
                        samples must be representative formalin-fixed paraffin-embedded  
                        (FFPE) tumor specimens in paraffin blocks (preferred) or at least  
                        10 unstained slides, with an associated pathology report, for  
                        correlative evaluation. Archival tissue for melanoma and lung   
                        cancer patients must be after PD1 exposure. 
 
8.2.2 BIOPSY 
 
Patients with biopsiable extracranial disease may have tissue collected pretreatment and at Cycle 2 (4 weeks after the 
start of treatment). An additional optional biopsy may be collected at Cycle 5, if accessible, but is not required. All 
biopsies are optional for enrollment, but highly encouraged for pretreatment and Cycle 2.  If standard of care biopsies 
are required, additional, optional tissue may be acquired as part of this protocol.  Acceptable samples include core-needle 
biopsies for deep tumor tissue (minimum of three cores) or excisional, incisional, or punch biopsies for cutaneous, 
subcutaneous, or mucosal lesions. 
 
 For core-needle biopsy specimens, at least three cores should be   
             submitted for evaluation.  Cores will be distributed to FFPE and  
             snap frozen equally.   
 
8.3 OPHTHALMOLOGY  

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OPHTHALMOLOGIC EXAMINATION MUST BE PERFORMED AT THE BASELINE, EVERY 12 WEEKS OF TREATMENT AND AT END 
OF TREATMENT. 
The objective of baseline ophthalmologic examination is to evaluate for evidence of retinal pathology that 
may be a risk factor for central serous retinopathy or RVO. Ophthalmologic examination must be performed 
by a qualified ophthalmologist. Riskfactors for RVO include uncontrolled serum cholesterol, 
hypertriglyceridemia, hyperglycemia, hypertension, and glaucoma. 
 
Baseline and serial surveillance ophthalmologic examination will include visual acuity testing, intraocular pressure 
measurements by tonometry, slit lamp ophthalmoscopy, indirect ophthalmoscopy, and Spectral-domain optical 
coherence tomography, if not available, may be substituted with time- domain optical coherence tomography. 
 
 
8.4 
LABORATORY ASSESSMENTS 
 
 
All labs will be processed locally at MDACC. 
 
8.5 
ELECTROCARDIOGRAM 
A standard 12-lead ECG will be performed using local standard procedures at Screening. Clinically significant abnormal 
findings should be recorded as medical history.  
Clinically significant abnormal findings seen on the follow-up ECGs should be recorded as adverse events. 
8.5.1   ECHO/MUGA 
An ECHO/MUGA will be done at baseline and every 2 months.   Please refer to Table 3.0 for additional information.  
Clinically significant abnormal findings seen on the follow-up ECHOs should be recorded as adverse events. 
8.6 
NEUROLOGICAL FUNCTION TESTING 

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Neurologic functioning will be evaluated using NANO. This objective and quantifiable assessment will evaluate nine major domains 
for subjects with brain tumors. The domains include: gait, strength, ataxia, sensation, visual field, facial strength, language, level of 
consciousness, behavior and overall. Each domain is rated on a scale of 0 to 3 where 0 represents normal and 3 represents the worst 
severity. A given domain should be scored non-evaluable if it cannot be accurately assessed due to preexisting conditions, co-morbid 
events and/or concurrent medications. The evaluation is based on direct observation/testing performed during routine office visits. The 
NANO scale will be completed by the principal investigator or designated study physician prior to dosing Day 1 Week 1 (baseline) 
and then at the time points indicated in on the schedule of events.  
Neuropsychological testing will be performed with a standardized battery routinely used to assess patients with brain metastases at 
MDACC, including in the previously published Chang et al. trial [55].  This evaluation will be performed by a trained psychometrist 
under the supervision of Dr. Wefel, a licensed, board certified clinical neuropsychologist in the Department of Neuro-Oncology. The 
following tests were selected because they are widely used, standardized psychometric instruments that have been shown to be 
sensitive to changes in neurologic disease as well as treatment effects of cancer treatment in other clinical trials.   Normative data have 
been published for all tests that take into account age, education, sex and handedness, where appropriate. These tests were also 
selected to minimize practice effects associated with repeated administration. The memory test has six alternate forms and the verbal 
fluency test has two alternate forms. The other tests measure motor and information processing speed and are relatively resistant to the 
effects of practice. 
 
The total time for neuropsychological testing, including the quality of life (QOL) and symptom measures, is about 45 minutes. 
 
 
 
 
 
 
Domain 
Test 
Administration 
Time 
(minutes) 
Memory 
Hopkins Verbal Learning Test-
Revised (HVLT-R) 
5  
Attention Span 
WAIS-IV Digit Span 
5 
Processing Speed 
Trail Making Test, Part A 
WAIS-IV Coding 
3 
3 

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Executive Function 
Trail Making Test, Part B 
5 
Verbal fluency 
Controlled Oral Word Association 
(COWA) 
5 
Motor Dexterity 
Lafayette Grooved Pegboard 
5 
 
 
 
PRO 
MD Anderson Symptom Inventory – 
Brain Tumor 
10 
 
 
 
 
ECOG Evaluation 
Eastern Cooperative Oncology Group (ECOG) Evaluation will be performed at Screening and at each cycle for every patient.  The 
principal investigator or qualified designee will assess ECOG status (see Appendix 4) at screening, additional time points for 
assessment of ECOG must be performed. 
8.7 
RESEARCH SAMPLE COLLECTION 
Samples for correlative studies may be collected as specified in the study calendar, processed and/or stored for analysis with 
optional subject consent. All tissue and resulting data will be de-identified and may be shared between MD Anderson and the 
study supporter (EMD). All samples and data will be tracked utilizing a unique research tracking number that will not be 
related to any patient identifying information. The sample collections will be reported in the database and a source document 
will be printed for monitoring purposes. Upon termination of the study, any remaining blood and tissue samples will be 
transferred and stored in the Melanona Tissue Bank (MelCore) for future use with an IRB approved protocol. 
Biospecimens will be collected accordint to the study calendar to evaluate the immunological effect of the treatment and SRS. 
Methods to evaluate this include but may not be limted to:  
• FACS on isolated PBMCs 
• Serum/plasma collection to assess circulating inflammatory cytokines 
• Single stain IHC. Markers include, but are not limited to: CD3, CD4, CD8, CD20 (B cell), CD1a (DC), CD11c 
(myeloid lineage), Granzyme B (cytotoxic CTLs and NK cells) FOXp3 (Treg cells) and CD3/CD8/CD45RO memory 
CTL (as proposed in the “Immunoscore” project); IDO and PD-L1 expression. 

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• Inflammatory expression pattern by Nanostring may be performed on the tumor tissue to mirror evaluations of 
cytokines and chemokines performed in the peripheral blood 
While mechanisms of resistance are relevant and central to all targeted therapy studies, the importance of this evaluation in our 
proposed study is in delineating the role of mechanisms of resistance assessed in extracranial metastatic melanoma tissues in 
predicting and describing the patterns of resistance intracranially. It is predicted that the presence or absence of resistance 
mechanisms extracranially may predict response and progression-free survival intracranially. 
Tissue availability permitting, we propose broad investigations on tissue biopsies comparing responders and non-responders, 
including whole exome sequencing, RNA expression analysis, and reverse phase protein array to examine markers of MAP 
kinase pathway activity, parallel signaling pathways, RTK activation, and pro and anti-apoptotic factors. 
Additionally, we may assess circulating free DNA from serial plasma/serum samples to determine patterns of response and early 
predictors of resistance. Finally, single  cell analyses (including  RNA sequencing) may be performed on CSF obtained. 
8.7.1 TISSUE 
 
Archival tumor tissue samples obtained outside of this study for other purposes will be collected, if available, from all patients. All 
samples must be representative formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks (preferred) or at 
least 10 unstained slides, with an associated pathology report, for local testing of tumor PD-L1 expression. 
 
Patients with biopsiable extracranial disease may have tissue collected pretreatment and at Cycle 2 (4 weeks after the start of 
treatment). Optional Biopsy may be collected at Cycle 5, if accessible, but is not required. If standard of care biopsies are required, 
additional, optional tissue may be acquired as part of this protocol. Acceptable samples include core-needle biopsies for deep 
tumor tissue (minimum of three cores) or excisional, incisional, or punch biopsies for cutaneous, subcutaneous, or mucosal lesions. 
Acceptable samples include core needle biopsies for deep tumor tissue or lymph nodes or excisional, incisional, punch, or forceps 
biopsies for cutaneous, subcutaneous, or mucosal lesions. For core-needle biopsy specimens, at least three cores should be 
submitted for evaluation. 
 
8.7.2 BLOOD 
Local laboratory assessments will include the following: 

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• Hematology (CBC, including RBC count, hemoglobin, hematocrit, WBC count, percent and absolute differential [neutrophils, 
bands, eosinophils, lymphocytes, monocytes, basophils, and other cells], and platelet count) 
• Serum chemistries (glucose, BUN, creatinine, sodium, potassium, magnesium, chloride, bicarbonate, calcium, phosphorus, 
total and direct bilirubin, ALT, AST, ALP, LDH, total protein, albumin, CPK, and uric acid) 
• Coagulation (aPTT and INR) 
• Pregnancy test (for women of childbearing potential, including women who have had a tubal ligation) 
• Urinalysis (specific gravity, pH, glucose, protein, ketones, and blood) 
• Serum samples for auto-antibody testing  (PK and ADA samples are all serum) 
PK 
PRIOR TO INFUSION AND IMMEDIATELY AFTER INFUSION (EOI) 
Cycle 1, day 1 and cycle 3 day 1 
PRIOR TO INFUSION  only: 
Cycle 2 and Cycle 6 OR end of treatment (whatever comes first) and followup visit if applicable 
 
ADA: 
PRIOR TO INFUSION only 
Cycle 1, day 1 ( PRETREATMENT); Cycle 3, day 1 and Cycle 6 OR end of treatment (whatever comes first) and followup 
visit if applicable 
 
• Blood samples for biomarker assays (up to 40 mls will be obtained to fulfill correlative biomarker plans) 
Additional Local Testing 
Perform the following tests as indicated in Study Flowchart (Table 3) and as clinically indicated. 
• Thyroid function testing (TSH, total T3, and free T4) 

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8.7.3 CEREBROSPINAL FLUID (CSF) 
 
CSF may be collected at the time of routine testing for Leptomeningeal disease (LMD). Leptomeningeal disease occurs when 
cancer cells migrate from your breast, lung, or some other part of your body to your cerebrospinal fluid (CSF).  CSF may be 
obtained at Cycle 1 Day 1 and Cycle 3 Day 3.  Patients will not be asked to undergo an optional lumbar puncture for the 
purposes of this study. At the time of diagnostic evaluation, additional CSF may be obtained for the purposes of this study. 
8.8 
TUMOR IMAGING AND ASSESSMENT OF DISEASE 
All subjects will undergo CT scanning and  MRI of the brain at the time points specified in the Schedule of Events. CT and 
MRI scans will be assessed locally per the modified RECIST 1.1, RANO-BM,and iRANO criteria. Up to 5 systemic and 5 
brain lesions will be followed for efficacy per the criteria. Patients with biopsiable extracranial disease may have tissue 
collected.   
 
8.9 
THERAPY ADMINISTRATION 
 
 
Drug 
Dose 
Dose 
Frequency 
Route of 
Administration 
Treatment 
Period 
Use 
Pimasertib 
30-60 mg 
BID 
Oral 
Continuously on 
28-day cycles 
Experimental 
Bintrafusp 
Alfa 
(M7824) 
1200 mg 
Every 2 
Weeks 
IV Infusion 
Once every 2 
Weeks on 28 
day cycles 
Experimental 
 
8.10 
MANAGEMENT OF PATIENTS WITH DISEASE PROGRESSION 
In the absence of unacceptable toxicity, patients who meet criteria for    disease progression will be permitted to continue study 
treatment if they meet all of the  
following criteria:  

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• Evidence of clinical benefit, as determined by the principal investigator following a review of all available data  
• Absence of symptoms and signs (including laboratory values) indicating unequivocal progression of disease  
• Absence of decline in ECOG Performance Status that can be attributed to disease progression  
• Absence of tumor progression at critical anatomical sites (e.g., leptomeningeal disease) that cannot be managed by protocol-
allowed medical interventions  
 
 
8.11 
SUPPORTIVE CARE GUIDELINES 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating principal investigator.  
Suggested supportive care measures for the management of adverse events with potential immunologic etiology are outlined 
below. Where appropriate, these guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of corticosteroids.   Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, 
attempts should be made to rule out other causes such as metastatic disease or bacterial or viral infection, which might require 
additional supportive care. The treatment guidelines are intended to be applied when the principal investigator determines the 
events to be related to pimasertib and bintrafusp alfa (M7824).  
Note: if after the evaluation the event is determined not to be related, the principal investigator does not need to follow the 
treatment guidance (as outlined below). Refer to Section for dose modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin photography as part of 
evaluation of the event. 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer additional anti-inflammatory measures, 
as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid administration. 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, abdominal pain, blood or 
mucus in stool, with or without fever) and of bowel perforation (such as peritoneal signs and ileus).   

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o All subjects who experience diarrhea/colitis should be advised to drink liberal quantities of clear fluids.  If sufficient 
oral fluid intake is not feasible, fluid and electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 Hyperglycemia, if associated 
with ketosis (ketonuria) or metabolic acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus and for Grade 3-4 hyperglycemia 
associated with metabolic acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, glycosylated hemoglobin, and C-
peptide.  
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of 
treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or liothyroinine, is indicated per 
standard of care. 
o Grade 3-4 hyperthyroidism  

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 Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and continued over no less than 4 weeks. 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks.  
• Ocular reactions:  
o Visual disturbances: for Grade 2 events, pimasertib should be discontinued until full resolution of the event and 
recovery of vision, assuming resolution of the event within 2 weeks to Grade 1 or less.  
o In case of visual symptoms but without vision loss, the treatment will not be discontinued. 
• Skin reactions:  
o Early introduction of oral tetracyclines and medium to high potency topical treatment (such as 1% hydrocortisone 
cream with moisteriser) should be initiated in case of Grade 1 or 2 skin reaction. The dose of the investigational 
treatment should not be decreased. 
o If a subject experiences a severe skin reaction (Grade ≥3), pimasertib therapy must be interrupted and may be resumed 
at the original dose when the reaction has resolved to Grade 1 or 2. In case of second or third occurrence of severe skin 
reaction pimasertib therapy must again be interrupted. Treatment may only resume at a lower dose level (45 mg BID 
after the second occurrence and 30 mg BID after the third occurrence) if the reaction has resolved to Grade 1 or 2. In 
case of further recurrence another dose reduction may be proposed. 
8.12 
PATIENT DISCONTINUATION 
 
THE PRIMARY REASON FOR STUDY TREATMENT DISCONTINUATION SHOULD BE DOCUMENTED IN THE SUBJECT’S CHART. PATIENTS WHO 
DISCONTINUE STUDY TREATMENT PREMATURELY WILL NOT BE REPLACED.  PATIENTS WHO DISCONTINUE FROM TREATMENT WILL BE 
ASKED TO RETURN TO THE CLINIC NO MORE THAN 30 DAYS AFTER THE LAST TREATMENT FOR A TREATMENT DISCONTINUATION VISIT.  THE 

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VISIT AT WHICH A RESPONSE ASSESSMENT SHOWS PROGRESSIVE DISEASE MAY BE USED AS THE TREATMENT DISCONTINUATION VISIT8.13
 
WITHDRAWAL 
 Subjects who discontinue/withdraw from treatment prior to completion of the treatment regimen should be encouraged to continue to 
be followed for all remaining study visits. However, patients have the right to voluntarily withdraw from the study at any time for any 
reason. In addition, the principal investigator has the right to withdraw a patient from the study at any time. Reasons for withdrawal 
from the study may include, but are not limited to the following:  
 
• Patient withdrawal of consent at any time  
• Any medical condition, determined by the principal investigator that may jeopardize the patient’s safety if he or she continues 
in the study  
• Patient becomes pregnant  
• Principal Investigator determines it is in the best interest of the patient  
• Patient non-compliance 
 
When a subject discontinues/withdraws from participation in the trial, all applicable activities scheduled for the final trial visit should 
be performed at the time of discontinuation. Any adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements. 
8.14 
END OF STUDY 
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the date at which the last data 
point required for statistical analysis or safety follow-up is received from the last patient, whichever occurs later. LPLV is 
expected to occur 24 months after the last patient is enrolled in the trial.  
8.15 
POST STUDY DRUG FOLLOW UP 
 
In this study, clinical benefit rate is the primary endpoint of the study. Post     
            study follow-up is of critical importance and is essential to preserving  
            subject safety and the integrity of the study. 
 
 
Subjects who discontinue study drug must continue to be followed for  
            collection of outcome and/or survival follow-up data as required by  
            phone every 12 weeks until death or the conclusion of the study. 
8.16 
LOST TO FOLLOW-UP 

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All reasonable efforts must be made to locate subjects to determine and  
            report their ongoing status. This includes follow-up with persons  
            authorized by the subject as noted above. Lost to follow-up is defined  
            by the inability to reach the subject after a minimum of three  
            documented phone calls, faxes, or emails as well as lack of response by  
            subject to one registered mail letter. 
 
 
All attempts should be documented in the subject’s medical records. If it is determined that the subject has died, the site will 
use permissible localmethods to obtain the date and cause of death. 
 
 
The site staff and PI will consult publicly available sources, such as  
public health registries and databases, in order to 
obtain updated contact  
information. If after all attempts, the subject remains lost to follow-up,   
            then the last known alive date as determined by the principal investigator     
            should be reported and documented in the subject’s medical records

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9.0  
STATISTICAL CONSIDERATIONS  
 
9.1 
PHASE I 
 
The phase I dose finding part of the study is to determine the recommended phase II dose (RP2D) 
of Bintrafusp Alfa (M7824) + Pimasertib in patients with intracranial metastasis. The planned DL1 
and DL2 doses are Bintrafusp Alfa (M7824) flat dose of 1200 mg every 2 weeks and Pimasertib 45 
mg PO BID (DL1) and 60 mg PO BID (DL2), and fallback doses DL-1 are Bintrafusp Alfa 
(M7824) flat dose of 1200 mg every 2 weeks and Pimasertib at 30 mg PO BID. We will enroll up 
to 12 patients to the Phase I portion (up to 18 can be enrolled should the trial de-escalate to DL-1). 
The standard “3+3” design will be employed to determine the RP2D. If DL1 is considered too 
toxic, DL-1 will be explored, if unacceptable toxicity is observed at DL-1, we will consider 
alternative schedules in discussion with EMD Serono. 
 
Dose limiting toxicity (DLT) is defined as below, including an intracranial and an extracranial 
DLT. These will be evaluated at 4 weeks after first administration of treatment.  
 
Intracranial DLT (T1):  Hypophysitis Grade ≥ 3; or neurologic toxicity Grade ≥3    
            
Extracranial DLT (T2):  Any Grade ≥ 3 adverse event outside CNS that is related  to 
Bintrafusp Alfa (M7824) or Pimasertib, occurring during the DLT evaluation period  
(Exceptions include: grade 3 flu-like symptoms or fever lasting less than a week,  
Grade 3 fatigue lasting less than a week, local reactions, headaches, nausea, and emesis leasting 
less than 72 hours, and grade 3 hemoglobin decrease (<8.0g/dL)).  
Elevated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) 3 times the upper 
limit of normal (ULN) range and a concomitant elevation of bilirubin 2 times the ULN attributable 
to study drug constitutes a DLT. 
 
 
 
The first cohort of 3 patients will be treated at Dose Level 1.  New cohorts of patients will not be 
treated until toxicity has been fully evaluated for all current patients.  
 
 
 
The algorithm is as follows at any dose level:  
 
1.  If 0 out 3 patients experiences DLT, the next cohort of 3 patients will be treated at the next 
higher dose level. 
2.  If 1 out of 3 patients experiences DLT, additional 3 patients will be treated at the same dose 
level. If no more than 1 out of 6 patients experiences DLT, the next cohort of 3 patients will be 
treated at the next higher dose level. 
  
3.  At any time, if greater than or equal to 2 out 3 or greater than or equal to 2 out 6  
patients experience DLT, another 3 patients will be treated at the next lower dose level if no more 
than 3 patients have been treated at the lower dose level. 
 
 
 
 
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The recommended phase II dose (RP2D) is defined as the highest dose level with no more than 1 
patient with DLT out of 6 patients that are treated. 
 
9.2 
PHASE II 
 
The purpose of phase II part is to estimate the time to intra-cranial progression and overall survival 
time.  In this part, we will enroll up to additional 24 patients into RP2D over the course of 12-18 
months.  The 6 patients treated at RP2D from phase I part of the study will be included in the Phase 
II part, thus resulting in a total of 30 patients at RP2D by the end of the study, with the goal of 
having 10 patients with each of melanoma, NSCLC, and breast cancer.  This phase II part is 
designed to collect data for future larger studies.  Specifically, we would like to estimate time to 
intracranial progression considering death as a competing risk and overall survival time using 
Kaplan-Meier method, both with 95% confidence interval. 
 
Two dose limiting toxicities (DLT) will be monitored separately: intracranial and extracranial 
DLTs. If there is a high chance that probability of intracranial DLT is found to be > 15%, i.e., 
Pr(intra-cranial DLT Rate > 15%|Data) > 70%, or the extra-cranial DLT rate of higher than 30%, 
i.e., Pr(extra-cranial DLT Rate > 30%|Data) > 70%, then the regimen will be considered too toxic 
at current dose. Results should be discussed with EMD Serono to decide if further enrollment 
should be started at a lower dose level.  Protocol will be amended if necessary.  The window for 
DLT evaluation will be at 4 weeks after the start of the treatment.  
 
Given these rules and the prior for intra-cranial DLT toxicity rate as beta(0.15, 0.85) and extra-
cranial DLT toxicity rate as beta(0.3, 0.7), we claim a dose level too toxic if any of the following 
happens. 
 
Number of patients with intra-cranial DLTs/total of number of patients treated >=3/10, 4/15, 5/20, 
5/25, 6/30; or 
 
Number of patients with extra-cranial DLTs/total of number of patients treated >=4/10, 6/15, 8/20, 
9/25, 11/30. 
 
The operating characteristics based on the toxicity stopping rules for 30 patients are in Table 4.  
The Bayesian toxicity monitoring rule are calculated by the online Shiny application Bayesian 
Toxicity Monitoring using posterior probability developed by Department of Biostatistics. The 
operating characteristics were evaluated using codes written by statistical collaborator Diane Liu. 
 
Table 4: Operating Characteristics (5,000 simulations) 
True Intracranial 
DLT Rate 
True Extracranial 
DLT Rate 
P (Stop Early) 
Average of Expected 
Sample Size 
0.05 
0.1 
0.03 
29 
0.05 
0.2 
0.17 
27 
0.05 
0.3 
0.50 
22 
0.05 
0.4 
0.82 
16 
0.05 
0.5 
0.97 
12 
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0.15 
0.1 
0.38 
25 
0.15 
0.2 
0.47 
23 
0.15 
0.3 
0.68 
19 
0.15 
0.4 
0.88 
14 
0.15 
0.5 
0.98 
11 
0.30 
0.1 
0.93 
14 
0.30 
0.2 
0.94 
13 
0.30 
0.3 
0.96 
12 
0.30 
0.4 
0.99 
11 
0.30 
0.5 
>0.99 
10 
 
9.3 
RESPONSE DEFINITIONS 
 
9.3.1 OVERALL SURVIVAL 
Overall survival (OS) is defined as the time from treatment start date to death.  Patients who are 
still alive at the end of the study will be censored.  PFS and OS will be assessed using the 
Kaplan-Meier method overall and by cohort. 
 
9.3.2 INTRACRANIAL PROGRESSION FREE SURVIVAL 
The time to intracranial progression, determined by modified RECIST 1.1 , will be calculated from 
the time of study enrollment to intracranial progression (event) or the last follow-up date if the 
patient has not developed the intracranial progression yet (censored).  The median time to 
intracranial progression and intracranial progression free survival rates at specific times will be 
estimated and reported with 95% confidence interval utilizing the method of Kaplan and Meier. 
This will serve as the primary analysis and will be performed overall and within each treatment 
group. Completing risk analysis may be considered by treating events outside of intracranial 
disease progression (e.g. events such as extracranial disease progression, early dropout due to 
toxicity, or death) as competing risks.   
 
9.3.3 TOXICITY 
The intracranial and extracranial toxicities and DLTs will be summarized by grade, relationship, 
time during the treatment, etc., for each dose in each group.   
 
9.3.4 EXTRACRANIAL PROGRESSION  
The time to extracranial progression, determined by RECIST 1.1 criteria, will be calculated from 
the time of study enrollment to extracranial progression (event) or the last follow-up date if the 
patient has not developed the extracranial progression yet (censored). The cumulative incidence 
rate may be estimated by competing risk analysis treating events outside of extracranial disease 
progression (e.g. events such as intracranial disease progression, early dropout due to toxicity, or 
death) as competing risks.   
 
9.3.5 EXTRACRANIAL RESPONSE RATE 
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The best achieved extracranial objective response rate will be reported for each patient. The 
frequency of extracranial objective response will be reported overall and within each treatment 
group. 
 
9.3.6 DURATION OF RESPONSE 
In patients who achieve extracranial, partial response (PR)or complete response (CR) via RECIST 
1.1 criteria, the time from date of first imaging identifying  PR or CR until the date of first imaging 
identifying progressive disease is noted will be recorded. Duration will be calculated utilizing the 
Kaplan-Meier method with reporting of the median and range overall and within each treatment 
group. 
 
9.3.7 STEROID REQUIREMENTS 
We will record and report steroid requirements for symptom management overall and within each 
treatment group. Patients who require at least 4 mg of dexamethasone/day for symptom 
management will be considered as requiring high dose steroids. 
 
9.3.8 OTHER ENDPOINTS 
Descriptive analysis will be provided to summarize the serum, tissue and imaging markers.  The 
relationship between the markers and response and/or toxicities may be evaluated using Kruskal-
Wallis test for continuous markers and Fisher’s exact test for discrete markers, when appropriate.  
The correlation between the serum/tissue markers and imaging parameters or between any two 
markers may also be assessed using Spearman correlation.  Given the size of the study, these 
analysis are exploratory in nature.   
 
Other statistical analysis methods may be applied when fit. 
 
The Principal Investigator is responsible for completing toxicity/efficacy summary reports and 
submitting them to the IND office Medical Affairs and Safety Group for review.  These should be 
submitted as follows:  
 
• Phase I: 
After the first 3 evaluable patients, complete 4 weeks of study treatment, and every 3 evaluable 
patients thereafter, IND Office approval must be obtained prior to advancing/changing dose levels. 
 
• Phase II: 
After the first 10 evaluable patients( including the six treated at RP2D from from phase I) complete 
4 weeks of study treatment, and every 5 patients thereafter. Also, a toxicity report will be submitted 
per cohort. 
  
 
A copy of the summary report should be placed in the Principal Investigator’s Regulatory Binder 
under “sponsor correspondence”. 
 
10.0 
ASSESSMENT OF SAFETY 
 
10.1 
ADVERSE EVENT ASSESSMENT AND REPORTING 
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An adverse event is defined as any untoward medical occurrence in a patient or clinical  
investigation subject administered a pharmaceutical product and which does not  
necessarily have to have a causal relationship with this treatment. An adverse event can  
therefore be any unfavorable and unintended sign (including an abnormal laboratory  
finding, for example), symptom, or disease temporally associated with the use of a  
medicinal product or protocol - specified procedure, whether or not considered related to  
the medicinal product or protocol specified procedure. Any worsening (i.e., any clinically  
significant adverse change in frequency and/or intensity) of a preexisting condition that is  
temporally associated with the use of the investigational products is also an adverse  
event. 
 
Changes resulting from normal growth and development that do not vary significantly in  
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants  
and children and onset of menses or menopause occurring at a physiologically  
appropriate time. 
 
 
Adverse events may occur during clinical trials or as prescribed in clinical practice, from  
overdose (whether accidental or intentional), from abuse and from withdrawal. 
 
 
Progression of the cancer under study is not considered an adverse event. 
 
 
From the time of initial protocol treatment through 30 days following cessation of  
treatment, all adverse events must be recorded. Such events will be recorded at each  
examination in the medical record. The reporting timeframe for adverse events meeting  
any serious criteria is described in Section 8.13. The principal investigator will make every attempt  
to follow all subjects with non–serious adverse events for outcome. 
 
The principal investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for subjects 
enrolled. 
 
 
An principal investigator who is a qualified physician will evaluate all adverse events  
according to the NCI Common Terminology for Adverse Events (CTCAE), version 5.0. 
Any adverse event which changes CTCAE grade over the course of a given episode will  
have each change of grade recorded on the adverse event case report forms/worksheets. 
 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 
Severity of the adverse events (AEs) -The severity of the adverse events (AEs) will be graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) V.5.0.  Events not included in the NCI CTCAE will be scored as follows: 
General grading: 
• Grade 1: Mild: discomfort present with no disruption of daily activity, no treatment 
required beyond prophylaxis. 
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• Grade 2: Moderate: discomfort present with some disruption of daily activity, require 
treatment. 
• Grade 3: Severe: discomfort that interrupts normal daily activity, not responding to first line 
treatment.  
• Grade 4: Life Threatening: discomfort that represents immediate risk of death 
 
 
 
For studies in which multiple agents are administered as part of a combination regimen, the 
principal investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may be 
assigned to a single agent if in the principal investigator’s opinion, there is sufficient data to 
support full attribution of the adverse experience to the single agent. 
 
 
 
All Adverse Events will be reported to regulatory authorities, IRB/IECs   
 
 
and principal investigators in accordance with all applicable global laws and  
 
regulations. 
 
Attribution - the determination of whether an adverse event is related to a medical treatment or 
procedure.  
• Definite - the adverse event is clearly related to the investigational agent(s). 
• Probable - the adverse event is likely related to the investigational agent(s). 
• Possible - the adverse event may be related to the investigational agent(s). 
• Unlikely - The adverse event is doubtfully related to the investigational agent(s). 
• Unrelated - The adverse event is clearly NOT related to the investigational agent(s).  
 
 
Recommended Adverse Event Recording Guidelines 
 
Attribution 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Unrelated 
Phase I 
Phase I 
Phase I 
Phase II   
 
Phase I 
Phase II   
Phase III 
Phase I  
Phase II   
Phase III 
Unlikely 
Phase I 
Phase I 
Phase I  
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Possible 
Phase I 
Phase II   
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Probable 
Phase I 
Phase II  
 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
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Definitive 
Phase I 
Phase II  
  
Phase I 
Phase II   
Phase III 
Phase I 
Phase II   
Phase III 
Phase I 
Phase II  
Phase III  
Phase I 
Phase II   
Phase III 
 
 
 
 
10.2 
SERIOUS ADVERSE EVENTS 
 
 
 
Serious Adverse Event (SAE) Reporting  
 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
principal investigator or the sponsor, it results in any of the following outcomes: 
 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the patient, in the 
view of the initial reporter, at immediate risk of death from the adverse experience as it occurred. 
It does not include an adverse experience that, had it occurred in a more severe form, might have 
caused death. 
• 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 that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples 
of such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
 
• Important medical events as defined above, may also be considered serious adverse events. Any 
important medical event can and should be reported as an SAE if deemed appropriate by the 
Principal Investigator or the IND Sponsor, IND Office. 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE must be 
reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”.   
• All SAEs, expected or unexpected/ initial or follow up, must be reported to the IND Office within 
5 working days of knowledge of the event regardless of the attribution. 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, must have 
a written report submitted within 24 hours (next working day) of knowledge of the event to the 
Safety Project Manager in the IND Office.   
• 
All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of 
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the event to the Safety Project Manager in the IND Office. 
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB. 
• The electronic SAE application (eSAE) will be utilized for safety reporting to the IND Office and 
MDACC IRB.  
• Serious adverse events will be captured from the time of the first protocol-specific intervention, 
until 90 days following cessation of treatment, or 30 days following cessation of treatment if the 
participant initiates new anticancer therapy, whichever is earlier unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there has 
been acceptable resolution of the event. 
• Additionally, any serious adverse events that occur after the 90 days following cessation of 
treatment, or 30 days following cessation of treatment if the participant initiates new anticancer 
therapy that are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
Pregnancy and Reporting 
 
If, following initiation of the investigational product, it is subsequently discovered that a study 
subject is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 6 half-lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety). The investigator must immediately notify EMD Serono of this event via the Pregnancy 
Surveillance Form in accordance with SAE reporting procedures within 24 hours. 
 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form [provided upon request from EMD Serono]. 
 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
EMD Serono. Information on this pregnancy will be collected on the Pregnancy Surveillance 
Form. 
 
Reporting Serious Adverse Events and Adverse Events of Special Interest Serious Adverse 
Events 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”. 
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Unless stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the 
IND Office, regardless of attribution (within 5 working days of knowledge of the event). 
 
SAEs, whether related or not related to study drug as detailed below, must be reported to EMD 
Serono within 5 working days from the time of knowledge of the event to: Pavithra Prasad, Fax: 
+49 6151 72 6914; E-mail: ICSR_CT_GPS@merckgroup.comIf only limited information is 
initially available, follow-up reports are required. (Note: Follow-up SAE reports should include 
the same investigator term(s) initially reported.) 
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 5 working days to the EMD 
Serono (or designee) using the same procedure used for transmitting the initial SAE report. 
 
All SAEs should be followed to resolution or stabilization. 
 
The principal investigator will ensure that all SAEs in the clinical database are reported to EMD 
Serono and any applicable health authority during the conduct of the study. 
 
SAEs will be reported on the EMD Serono approved form for prompt reporting (full form): 
“Internal SAE Report Form for Prompt Reporting” Institutional Review Board. 
SAEs will be submitted to both the Office of Protocol Research, Unit 1437 at The University of 
Texas MD Anderson Cancer Center and also sent to:
All SAEs should be faxed or e-mailed to EMD  Serono to: 
Fax: +49 6151 72 6914; E-mail: ICSR_CT_GPS@merckgroup.com 
 
 
10.3 
EVENTS OF CLINICAL INTEREST 
 
Selected non-serious and serious adverse events are also known as Events  of Clinical 
Interest (ECI) and must be reported within 2 working days.   
 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any participant 
must be reported within 2 working days if it causes the participant to be excluded from 
the trial, or is the result of a protocol-specified intervention, including but not limited to 
washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
 
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the 
participant initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to 
an ECI, whether or not related to product, must be reported within 2 working days.   
 
Events of clinical interest for this trial include: 
1.  an overdose of product, as defined in Section 10.4, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
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upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  In addition, please note that “Events 
of Clinical Interest” including pregnancy, will be reported via eSAE application as 
“Other Important Medical Event”, to the IND Office. 
 
10.4 
DEFINITION AND REPORTING OF AN OVERDOSE FOR THIS PROTOCOL 
For this study, any dose of bintrafusp alfa greater than 2 times (i.e., > 2400 mg) more than the 
planned dose administered within a 24-hour time period will be considered an overdose.  
No specific information is available on the treatment of overdose of this drug. In the 
event of overdose, the participant should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
 
 
10.5 
REPORTING OF PREGNANCY AND LACTATION 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of principal investigators or their designees to report any 
pregnancy or lactation in a participant (spontaneously reported to them) that occurs 
during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the consent form 
is signed but before treatment allocation/randomization must be reported by the principal 
investigator if they cause the participant to be excluded from the trial, or are the result of 
a protocol-specified intervention, including but not limited to washout or discontinuation 
of usual therapy, diet, placebo treatment or a procedure.   
 
Pregnancies and infant exposures during breastfeeding that occur from the time of 
treatment allocation/randomization through 120 days following cessation of 
investigational product, or 30 days following cessation of treatment if the participant 
initiates new anticancer therapy, whichever is earlier, must be reported by the principal 
investigator.  All reported pregnancies must be followed to the completion/termination of 
the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and 
stillbirth must be reported as serious events (Important Medical Events). If the pregnancy 
continues to term, the outcome (health of infant) must also be reported. 
11.0 
ADMINISTRATIVE AND REGULATORY DETAILS 
 
11.1 
INVESTIGATOR COMMUNICATIONS 
 
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All reports of overdose, pregnancy, lactation, SAEs, and ECIs must be reported within 2 
working days to the MDACC IND Office via eSAE application as “Other Important 
Medical Events.” 
 
Additionally, any reportable event, considered by principalinvestigator, who is a qualified 
physician, to be related to product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period also 
must be reported.   
 
 
11.2 
INVESTIGATOR RESPONSIBILITY FOR REPORTING EVENTS 
All Adverse Events will be reported to regulatory authorities and IRB/IECs in accordance 
with all applicable global laws and regulations. 
 
11.3 
DATA MANAGEMENT 
 
 
11.3.1   DATA COLLECTION 
The study coordinator and principal investigators are responsible for ensuring that the 
eligibility checklist is completed in a legible and timely manner for every patient enrolled 
in the study, and that data are recorded on the appropriate forms and in a timely manner 
in the electronic case report forms (eCRFs) in the Prometheus database. Please note that 
CORe (Clinical Oncology Research System) will be used to register patients enrolled on 
the study.  All source documents will be available for inspection by the FDA and the 
MDACC IRB.  
 
 
 
11.3.2   DATA SAFETY MONITORING PLAN 
Principal Investigator, Sub-investigators, regulatory, CRS management, clinical research 
coordinators, clinical research associates, data managers, and clinic staff meet monthly 
to review and discuss study data to include, but not limited to, the following: 
• serious adverse events 
• subject safety issues 
• recruitment issues 
• accrual 
• protocol deviations 
• unanticipated problems 
• breaches of confidentiality 
Toxicity will be monitored as outlined in the statistical Section 9.0. All toxicities 
encountered during the study will be evaluated on an ongoing basis according to the 
NCI Common Toxicity Criteria version 5. All study treatment associated adverse 
events that are serious, at least possibly related and unexpected will be reported to the 
IRB. Any modifications necessary to ensure subject safety and decisions to continue, or 
close the trial to accrual are also discussed during these meetings. If any literature 
becomes available which changes the risk/benefit ratio or suggests that conducting the 
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trial is no longer ethical, the IRB will be notified in the form of an Unanticipated 
Problem submission and the study may be terminated. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies 
for reporting unanticipated problems involving risk to subjects or others (including 
adverse events). 
 
All records related to this research study will be stored in a locked environment. Only 
the researchers affiliated with the research study and their staff will have access to the 
research records. 
 
 
11.3.3  
   DATA HANDLING AND RECORD KEEPING 
The P ri n ci p al  Investigator (i.e., the study site Investigator) will maintain records 
in accordance with Good Clinical Practice. 
 
The MDACC investigator will retain the MDACC-IND records for 5 years after study 
closure.   
INSTITUTIONAL REVIEW BOARD (IRB) APPROVAL 
The principal investigator (i.e., the study site Investigator) will obtain, from the MD 
Anderson Cancer Center Institutional Review Board (IRB), prospective approval of the 
clinical protocol and corresponding informed consent form(s); modifications to the 
clinical protocol and corresponding informed consent forms, and advertisements (i.e., 
directed at potential research subjects) for study recruitment, if applicable. 
 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval 
is to eliminate an apparent immediate hazard to the research subject(s). In such 
circumstances, the principal investigator will promptly notify the MD Anderson Cancer 
Center IRB of the deviation. 
 
The MD Anderson Cancer Center IRB operates in compliance with FDA regulations at 
21 CFR Parts 50 and 21 CFR 56, and in conformance with applicable International 
Conference on Harmonization (ICH) Guidelines on Good Clinical Practice. 
COMPLIANCE WITH TRIAL REGISTRATION AND RESULTS 
POSTING REQUIREMENTS 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and 
the Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, 
http://www.clinicaltrials.gov.  Information posted will allow subjects to identify 
potentially appropriate trials for their disease conditions and pursue participation by 
calling a central contact number for further information on appropriate trial locations and 
trial site contact information. 
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11.3.4    ETHICAL CONSIDERATIONS 
The clinical study will be conducted in accordance with the current IRB- approved 
clinical protocol; ICH Guidelines on Guidelines on Good Clinical Practice; and 
relevant policies, requirements, and regulations of the University of Texas MD 
Anderson Cancer Center IRB, and applicable federal agencies. 
11.3.5 INFORMED CONSENT 
The investigator (i.e., the study site Investigator) will make certain that an appropriate 
informed consent process is in place to ensure that potential research subjects, or their 
authorized representatives, are fully informed about the nature and objectives of the 
clinical study, the potential risks and benefits of study participation, and their 
rights as research subjects. The investigator, or a sub-investigator(s) designated by the 
MD Anderson IND Office, will obtain the written, signed informed consent of each 
subject, or the subject’s authorized representative, prior to performing any study-
specific procedures on the subject. The date and time that the subject, or the subject’s 
authorized representative, signs the informed consent form and a narrative of the 
issues discussed during the informed consent process will be documented in the 
subject’s case history. The investigator or sub-investigator will retain the original copy 
of the signed informed consent form, and a copy will be provided to the subject, or 
to the subject’s authorized representative. 
12.0 
STUDY DOCUMENTATION, MONITORING, AND ADMINISTRATION 
The principal investigator and the head of the medical institution (where applicable) 
agrees  to allow the IND Office monitor direct access to all relevant documents and to 
allocate their time and the time to their staff to monitor to discuss findings and any issues. 
 
Monitoring visits will be conducted in a manner to ensure that the: 
• 
Data are authentic, accurate, and complete. 
• 
Safety and rights of subjects are being protected. 
• 
Study is conducted in accordance with the currently approved protocol and 
 
any other study agreements, ICH GCP, and all applicable regulatory 
 
requirements. 
 
 
 
 
 
 
 
 
 
 
 
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APPENDICES 
 
Appendix 1: immunotherapy Response Assessment for Neuro-Oncology (iRANO) 
Modified Excerpt from Original Publication 
Selected sections from the immunotherapy Response Assessment for Neuro-Oncology 
(iRANO), are presented below. 
For the purposes of the current study, we will use a modified version of iRANO 
(modified iRANO) that allows intracranial tumors that are >0.5 and <1.0 cm 
assessed by MRI to be considered measurable disease. This will be the only 
modification. 
iRANO Criteria 
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The iRANO guidelines incorporate criteria previously deﬁned by the RANO working 
committee to deﬁne complete response, partial response, minor response, stable disease, 
progressive disease, and non-evaluable disease for patients with malignant glioma,16 
low-grade glioma,40 and brain metastases.18 The key component of the iRANO criteria 
is speciﬁc additional guidance for the determination of progressive disease in patients 
with neuro-oncological malignancies undergoing immuno- therapy (table 1, ﬁgure 3). 
Speciﬁcally, the iRANO criteria advocate for the conﬁrmation of radiographic progression in 
appropriate patients deﬁned by clinical status and time from initiation of immunotherapy. 
In patients who have imaging ﬁndings that meet RANO criteria for progressive disease16–
18 within 6 months of starting immunotherapy including the development of new lesions, 
conﬁrmation of radiographic progression on follow-up imaging before deﬁning the patient 
as non- responsive to treatment might be needed provided that the patient does not have 
new or substantially worse neurological deﬁcits. Such patients might be allowed a 
window of 3 months before conﬁrming disease progression with the scan that ﬁrst 
showed initial progressive  changes  as  the  new  reference  scan for comparison with 
subsequent imaging studies. If RANO criteria for progressive disease are met on the 
follow-up scan 3 months later, non-responsiveness to treatment should be assumed, and 
the date of progressive disease should be back-dated to the initial date when it was ﬁrst 
identiﬁed (table 1). Patients who develop substantial new or worsened neurological deﬁcits 
not due to comorbid events or a change in co-administered medication at any time within 
the 3-month follow-up window should be designated as non-responsive to treatment and 
should discontinue immunotherapy. For these patients, the date of actual tumor 
progression should also be back-dated to the date when radiographic progressive disease 
was initially identiﬁed. 
 
RANO and iRANO criteria (Brain Metastases) 
 
Brain metastases 
COMPLETE 
TARGET 
Disappearance of all enhancing target and non-lesions for ≥4 
weeks; no new lesions; no steroids; clinically stable or improved 
PARTIAL 
RESPONSE 
≥30% decrease in sum of longest diameters of target lesions for ≥4 
weeks; no new lesions; stable or decreased steroid dose; clinically 
stable or improved 
MINOR RESPONSE 
NA 
STABLE DISEASE 
Does not qualify for complete response, partial response, or 
progressive disease 
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PROGRESSIVE 
DISEASE 
≥20% increase in the sum of longest diameters of target lesions; 
or unequivocal progression of enhancing non-target lesions; or 
new lesions; or substantial clinical decline 
The iRANO criteria integrate into the existing RANO criteria for malignant glioma, 
low-grade glioma, and brain metastases by providing recommendations for the 
interpretation of progressive imaging changes. Speciﬁcally, iRANO recommends 
conﬁrmation of disease progression on follow-up imaging 3 months after initial radiographic 
progression if there is no new or substantially worsened neurological deﬁcits that are not due 
to comorbid events or concurrent medication, and it is 6 months or less from starting 
immunotherapy. If follow-up imaging conﬁrms disease progression, the date of actual 
progression should be back-dated to the date of initial radiographic progression. The 
appearance of new lesions 6 months or less from the initiation of immunotherapy alone 
does not deﬁne progressive disease. FLAIR=ﬂuid-attenuated inversion recovery. 
iRANO=immunotherapy Response Assessment in Neuro-Oncology. N/A=not applicable. 
 
 
 
 
 
 
 
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If radiographic ﬁndings at the 3-month follow-up meet RANO criteria for stable disease, 
partial response, or complete response16–18 compared with the original scan meeting 
criteria for progression, and no new or worsened neurological deﬁcits are identiﬁed, such 
patients should be deemed as deriving clinical beneﬁt from therapy and allowed to 
continue treatment. Patients who develop worsening radiographic ﬁndings compared with 
the pre- treatment baseline scan more than 6 months from starting immunotherapy are 
expected to have a 
low likelihood of 
ultimately deriving 
clinical beneﬁt and 
should be regarded 
as non-responsive to 
treatment with a 
recommendation to 
discontinue therapy. 
Overall, we have 
integrated guidance 
from the immune-
related response 
criteria regarding 
interpretation of 
progressive imaging 
findings with 
existing RANO 
criteria to form the 
iRANO guidelines. 
A comparison of the 
key features 
associated with 
RANO, immune-
related response 
criteria, and iRANO 
are summarized 
(table 2). Although 
application of 
immunotherapies 
for patients with neuro-oncology malignancies is in the early stages of development and 
much remains to be learned, the iRANO criteria provides guidelines that can be applied 
to provide consistent metrics in clinical trials and daily practice. Particularly, these 
guidelines shall raise awareness of the possibility of potentially misleading early 
progressive radiographic changes after initiation of immunotherapy, and provide 
guidance for responding to these changes to decrease the likelihood of inappropriate 
Yes 
No 
>6 months 
≤6 months 
as long as no signiﬁcant clinical decline 
unrelated to 
Repeat imaging 3 months after initial imaging 
 
Discontinue current 
 
Patient classiﬁed as having progressive 
Figure a: iRANO treatment algorithm for the assessment of progressive imaging ﬁndings in patients with 
neuro-oncological malignancies undergoing immunotherapy 
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premature therapy discontinuation. We expect the iRANO guidelines will be amended 
successively to improve their usefulness as further experience and systematic data from 
continuing immunotherapy trials in neuro-oncology accumulate. 
Key Considerations for RANO Criteria, Immune-Related Response Criteria, and 
iRANO Criteria 
 
 
RANO 
Immune-
related 
response 
criteria 
iRANO (if 
therapy ≤6 
months after 
start of 
immunotherapy 
iRANO (if >6 
months after 
start of 
immunotherapy) 
Is a repeat scan needed 
to conﬁrm 
radiographic 
progressive disease for 
patients without 
signiﬁcant clinical 
decline? 
No 
Yes 
Yes 
No 
Minimum time interval 
for conﬁrmation of 
disease progression for 
patients without 
signiﬁcant clinical 
decline 
 
NA 
≥ 4 weeks 
≥ 3 months 
NA 
Is further 
immunotherapy 
treatment allowed after 
initial radiographic 
progressive disease (if 
clinically stable) 
pending disease 
progression 
conﬁrmation? 
 
NA 
YES 
Yes 
NA 
Does a new lesion 
deﬁne progressive 
disease? 
 
Yes 
No 
No 
Yes 
 iRANO=immunotherapy Response Assessment in Neuro-Oncology. N/A=not 
applicable. 
 
  
 
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Appendix 2 
 
 
Response Evaluation Criteria in Solid Tumors (RECIST v1.1 Criteria) 
The RECIST criteria should be used to assess response to treatment. Only patients with 
measurable disease should be entered in the study. Measurable extracranial disease is 
defined as the presence of one lesion that can be accurately measured in at least one 
dimension (longest diameter to be recorded) as ≥2.0 cm with conventional techniques (or 
as ≥1.0 cm by spiral CT). Evaluable lesions should be followed for the assessment of 
response. Non-measurable lesions include bone lesions, ascites, pleural/pericardial 
effusion, lymphangitic carcinomatosis, abdominal masses that are not confirmed by CT, 
and cystic lesions. Disease progression and response evaluations for intracranial and 
extracranial disease will be determined according to the definitions established in the 
Response Evaluation Criteria in Solid Tumours (RECIST v1.1). Minor modifications will 
be applied to the assessment of intracranial lesions: 
• General: target lesions should be representative of the subject’s baseline tumor burden 
and should be selected based on their size (i.e. lesions with the longest diameter) and 
their suitability for accurate repeat assessment. 
• Intracranial lesions: (the modifications to RECIST v1.1. impact the number and the 
minimal size of the target lesions selected at baseline) up to five lesions should be 
selected as target lesions; all brain lesions in excess of these five target lesions have to 
be regarded as non-target lesions. Measurable lesions are defined as those that can be 
accurately measured in at least one dimension with the longest diameter ≥ 5 mm when 
evaluated with contrast-enhanced MRI. Contrast-enhanced MRI is the only imaging 
modality accepted for assessment of intracranial lesions. 
• Extracranial lesions: up to two lesions per organ representative of all involved organs 
should be selected as target lesions; the total number of target lesions should not exceed 
five and all lesions in excess of these five target lesions have to be regarded as non-
target lesions. 
 
Baseline Documentation of Intracranial Target and Non-Target Lesions 
• All baseline lesion assessments must be performed within 28 days of the first dose of 
study treatment. 
• Measurable and non-measurable intracranial (i.e. brain parenchyma) lesions up to a 
maximum of 5 lesions should be identified as target lesions, and recorded and 
measured at baseline. These lesions should be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). 
• Cystic lesions thought to represent cystic metastases should not be selected as target 
lesions when other suitable target lesions are available. 
• Measurable intracranial lesions that have been previously irradiated and have not 
been shown to be progressing following irradiation should not be considered as target 
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lesions. All other intracranial lesions should be identified as non-target and should 
also be recorded at baseline. Measurements of non-target lesions are not required, but 
the presence or absence of each should be noted throughout follow-up. 
Baseline Documentation of Extracranial Target and Non-Target Lesions 
• All baseline lesion assessments must be performed within 28 days of the first dose of 
study treatment.  
• Lymph nodes that have a short axis of <10mm are considered non-pathological and 
should not be recorded or followed. 
• Pathological lymph nodes with <15mm and ≥10mm short axis are considered non 
measurable. 
• Pathological lymph nodes with ≥15mm short axis are considered measurable and can 
be selected as target lesions, however lymph nodes should not be selected as target 
lesions when other suitable target lesions are available. 
• Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved extracranial organs, should be identified as target lesions, 
and recorded and measured at baseline. These lesions should be selected on the basis 
of their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically). 
• Cystic lesions thought to represent cystic metastases should not be selected as target 
lesions when other suitable target lesions are available. 
• Measurable extracranial lesions that have been previously irradiated and have not been 
shown to be progressing following irradiation should not be considered as target lesions. 
• Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by CT or MRI can be considered measurable. 
• Bone scans, FDG-PET scans or X-rays are not considered adequate imaging techniques 
to measure bone lesions. 
• All other lesions (or sites of disease, excluding the brain) should be identified as non-
target and should also be recorded at baseline. 
• Non-target lesions will be grouped by organ. Measurements of these lesions are not 
required, but the presence or absence of each should be noted throughout follow-up. 
Overall Intracranial Response - Evaluation of Intracranial Target Lesions 
Definitions for assessment of response for intracranial target lesion(s) are as follows: 
• Complete Response (CR): Disappearance of all target lesions. 
• Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as a reference, the baseline sum of the diameters (e.g. percent change 
from baseline). 
• Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease. 
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• Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as a reference, the smallest sum of diameters recorded since the 
treatment started (e.g. percent change from nadir, where nadir is defined as the smallest 
sum of diameters recorded since treatment start). In addition, the sum must have an 
absolute increase from nadir of 5mm. 
• Not Evaluable (NE): Cannot be classified by one of the four preceding definitions. 
Note: If an intracranial target lesion disappears and reappears at a subsequent time 
point it should continue to be measured. The response at the time when the lesion 
reappears will depend upon the status of the other lesions. For example, if the 
disease had reached a CR status then PD would be documented at the time of 
reappearance. However, if the response status was PR or SD, the diameter of the 
reappearing lesion should be added to the remaining diameters and response 
determined based on percent change from baseline and percent change from nadir. 
• Patients, who in the opinion of the treating physician investigator have had a 
substantial decline in their performance status and have clinical evidence of 
progressive disease may be classified as having progressive disease. 
 
 
Appendix 2: Current National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE Version 5.0) 
 
Please use the following link to the NCI CTCAE website: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 
 
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Appendix 3: Eastern Cooperative Oncology Group (ECOG) Performance Status 
Scale 
 
Grade 
Description 
0 
Fully active, able to carry on all pre-disease performance without 
restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to 
carry out work of a light or sedentary nature, e.g., light housework or 
office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about > 50% of waking hours 
3 
Capable of only limited self-care, confined to a bed or chair > 50% of 
waking hours 
4 
Completely disabled; cannot carry on any self-care; totally confined to 
bed or chair 
5 
Dead 
 
 
 
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Appendix 4: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
• Pre-menarchal 
• Premenopausal female with 1 of the following: 
• Documented hysterectomy 
•  
Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
• Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause.  
o A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or hormonal replacement therapy (HRT). 
However, in the absence of 12 months of amenorrhea, confirmation with 
two FSH measurements in the postmenopausal range is required.  
 
• Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment. 
 
CONTRACEPTION REQUIREMENTS 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate 
if they agree to one of the following during the protocol as defined:  
● Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
● Use a male condom plus partner use of a contraceptive method with a failure rate of 
<1% per year as described in Table 5 when having penile-vaginal intercourse with a 
woman of childbearing potential who is not currently pregnant. 
○ Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each 
episode of penile penetration. 
 
Table 2: Highly Effective Contraceptive Methods That Have Low User Dependency 
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant a, b 
● Intrauterine hormone-releasing system (IUS) b 
● Intrauterine device (IUD) 
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● Bilateral tubal occlusion 
 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.  
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods 
for participants of clinical studies. 
 
a) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) 
guidelines, acceptable contraceptive implants are limited to those which inhibit ovulation. 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least 120 days, corresponding to time needed to eliminate study 
treatment plus 30 days for study treatments with genotoxic potential]  after the last dose of 
study treatment.   
 
 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to 
use a highly effective method of contraception consistently and correctly as described in 
Table 6 during the protocol-defined time frame.   
 
Table 3: Highly Effective Contraception Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing ) hormonal contraception b, c 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
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● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently 
and correctly).  
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least 120 days, corresponding to time needed to eliminate study 
treatment plus 30 days for study treatments with genotoxic potential]  after the last dose of 
study treatment . 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
PREGNANCY TESTING 
WOCBP should only be included after a negative highly sensitive urine or serum 
pregnancy test and in accordance with local requirements.  When applicable, this test 
should be repeated a maximum of 24-hours before the first dose/vaccination. 
Following initiation of treatment additional pregnancy testing will be performed at Day 1 
of every 4 week cycle during the treatment period and at 120 days after the last dose of 
study treatment and as required locally. 
 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected. 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 6 
 
NCCN GUIDELINES FOR TREATMENT OF CANCER 
 
 
 
https://www.nccn.org/professionals/physician_gls/default.aspx 
 
 
 
 
Appendix 7 
 
 
AMERICAN SOCIETY OF CLINICAL ONCOLOGY CLICINAL PRACTICE 
GUIDELINES 
 
 
https://www.asco.org/practice-guidelines/quality-guidelines/guidelines 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 8 
 
 
Neurologic Assessment in Neuro-Oncology (NANO) Scale 
 
Scoring assessment is based on direct observation and testing performed during clinical 
evaluation and is not based on historical information or reported symptoms. Please check 
one answer per domain. Please check “Not assessed” if testing for that domain is not 
done. Please check “Not evaluable” if a given domain cannot be scored accurately 
because of preexisting conditions, comorbid events, or concurrent medications. 
 
 
Patient identifier:   
                   Date assessment performed (day/month/year):                                       
Study time point (ie, baseline, cycle 1, day 1, etc):     
Assessment performed by (please print name):   
 
 
 
 
Domains 
Key Considerations 
 
 
Gait 
0 
Normal 
1 
Abnormal but walks without assistance 
2 
Abnormal and requires assistance (companion, cane, walker, etc.) 
3 
Unable to walk Not assessed Not evaluable 
 
Strength 
0 
Normal 
1 
Movement present but decreased against resistance 
2 
Movement present but none against resistance 
3 
No movement Not assessed Not evaluable 
  
 
Ataxia (Upper Extremity) 
0 
Able to finger-to-nose touch without difficulty 
1 
Able to finger-to-nose touch but difficult 
2 
Unable to finger-to-nose touch Not assessed 
Not evaluable 
 
 
Sensation 
0 
Normal 
1 
Decreased but aware of sensory modality 
2 
Unaware of sensory modality Not assessed 
Not evaluable 
 
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Visual Fields 
0 
Normal 
1 
Inconsistent or equivocal partial hemianopsia (≥quadrantanopsia) 
2 
Consistent or unequivocal partial hemianopsia (≥quadrantanopsia) 
3 
Complete hemianopsia Not assessed 
Not evaluable 
 
 
Facial Strength 
0 
Normal 
1 
Mild/moderate weakness 
2 
Severe facial weakness Not assessed 
Not evaluable 
  
 
Language 
0 
Normal 
1 
Abnormal but easily conveys meaning to examiner 
2 
Abnormal and difficulty conveying meaning to examiner 
3 
Abnormal; if verbal, unable to convey meaning 
to examiner; OR nonverbal (mute/global aphasia) Not assessed 
Not evaluable 
 
 
Level of Consciousness 
0 
Normal 
1 
Drowsy (easily arousable) 
2 
Somnolent (difficult to arouse) 
3 
Unarousable/coma Not assessed 
Not evaluable 
 
 
Behavior 
0 
Normal 
1 
Mild/moderate alteration 
2 
Severe alteration Not assessed Not evaluable 
 
 
 
 
 
 
 
 
 
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Appendix 9 
 
Assessment of Quality of Life (QOL) 
 
https://www.aqol.com.au/documents/AQoL-8/AQoL-8_questionnaire.pdf 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 10   Pill Diary 
 
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Pimasertib 
Comments 
 
AM 
PM 
 
Date 
of 
Dose 
Day 
Month 
Year 
Time 
of 
Dose 
Hr:Min 
00:00-
23:59 
Dose 
 
 
mg 
Time 
of 
Dose 
Hr:Min 
00:00-
23:59 
Dose 
 
 
mg 
Patient comments for side 
effects related to drugs 
e.g., 06 
JAN 11 
07:30 
60 
18:15 
60 
Nausea 
1. 
 
 
 
 
 
2. 
 
 
 
 
 
3. 
 
 
 
 
 
4. 
 
 
 
 
 
5. 
 
 
 
 
 
6. 
 
 
 
 
 
7. 
 
 
 
 
 
8. 
 
 
 
 
 
9. 
 
 
 
 
 
10. 
 
 
 
 
 
11. 
 
 
 
 
 
12. 
 
 
 
 
 
13. 
 
 
 
 
 
14. 
 
 
 
 
 
15. 
 
 
 
 
 
16. 
 
 
 
 
 
17. 
 
 
 
 
 
18. 
 
 
 
 
 
19. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pimasertib 
Comments 
 
AM 
PM 
 
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Patient Signature: ____________________________ 
Date: ___________________ 
 
The Physician’s Office will complete this section: 
 
1. Start date: ____________________                   End date:  
___________________________ 
2. Total 
number 
of 
pills 
dispensed 
 
this 
cycle:_____________________________________ 
3. Total 
number 
of 
pills 
taken 
 
this 
cycle: 
________________________________________ 
4. Total 
number 
of 
pills 
returned 
 
this 
cycle:______________________________________ 
 
Physician/Nurse 
Signature:________________________________________________________ 
 
 
Comments:_________________________________________________________________
____ 
 
Date 
of 
Dose 
 
 
 
Day 
Month 
Year 
Time 
of 
Dose 
Hr:Min 
00:00-
23:59 
Dose 
 
 
mg 
Time 
of 
Dose 
Hr:Min 
00:00-
23:59 
Dose 
 
 
mg 
Patient comments for side 
effects related to drugs 
e.g., 06 
JAN 11 
07:30 
60 
18:15 
60 
Nausea 
21. 
 
 
 
 
 
22. 
 
 
 
 
 
23. 
 
 
 
 
 
24. 
 
 
 
 
 
25. 
 
 
 
 
 
26. 
 
 
 
 
 
27. 
 
 
 
 
 
28. 
 
 
 
 
 
29. 
 
 
 
 
 
30. 
 
 
 
 
 
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13.0 
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