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evaluation of target lesions

| Complete Response (CR)   | Disappearance of all non-target lesions and normalization  of tumor marker level. All lymph nodes must be nonpathological in size (<10 mm short axis) Note: If tumor markers are initially above the upper  normal limit, they must normalize for a subject to be  considered in complete clinical response.   |
|--------------------------|---|  
| Non-CR/ Non-PD           | Persistence of one or more non-target lesion(s) and/or  maintenance of tumor marker level above the normal  limits                                                                                                                                                         |
|--------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Progressive Disease (PD) | Appearance of one or more new lesions and/or  unequivocal progression of existing non-target lesions.  Unequivocal progression should not normally trump  target lesion status. It must be representative of overall  disease status change, not a single lesion increase. |  
Although a clear progression of "non-target" lesions only is exceptional, the opinion of the investigator should prevail in such circumstances, and the progression status should be confirmed by scans in 6 weeks.
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evaluation of best overall response

The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). In general, the subject's best response assignment will depend on the achievement of both measurement and confirmation criteria.  
| Target Lesions                                                                                                        | Non-Target Lesions           | New Lesions   | Overall Response   |
|-----------------------------------------------------------------------------------------------------------------------|------------------------------|---------------|--------------------|
| CR                                                                                                                    | CR                           | No            | CR                 |
| CR                                                                                                                    | Non-CR/ Non-PD               | No            | PR                 |
| CR                                                                                                                    | Not evaluated                | No            | PR                 |
| PR                                                                                                                    | Non-PD/ or not all evaluated | No            | PR                 |
| SD                                                                                                                    | Non-PD or not all evaluated  | No            | SD                 |
| Not all evaluated                                                                                                     | Non-PD                       | No            | Non-evaluable      |
| PD                                                                                                                    | Any                          | Yes or No     | PD                 |
| Any                                                                                                                   | PD*                          | Yes or No     | PD                 |
| Any                                                                                                                   | Any                          | Yes           | PD                 |
| *In exceptional circumstances, unequivocal progression in non-target lesions may be  accepted as disease progression. |                              |               |                    |  
Subjects with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be classified as having "symptomatic deterioration". Every effort should be made to document the objective progression even after discontinuation of treatment.  
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. When the evaluation of complete response depends on this determination, it is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status.
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definitions for response evaluation

- **Objective response rate (ORR)** defined as the proportion of all treated subjects whose best response at any time during the study following initiation of therapy is confirmed CR or confirmed PR. This will be assessed according to the RECIST v1.1
- **Progression free survival (PFS)** defined as the time between the first dose of study therapy and the earliest date of confirmed progression or death. Subjects who have neither progressed nor died will be censored at the last tumor assessment date for PFS.  
- **Disease control rate (DCR)** defined as the percentage of patients achieving CR + PR + SD at any time during the study following initiation of therapy. This will be assessed according to RECIST
v1.1 criteria.  
- Overall survival **(OS)** defined as the time between the first dose of study therapy and death
(subjects who have not died will be censored at the most recent last-known-alive date), will also be analyzed.
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8.2 safety assessments

- An investigator who is a qualified physician will evaluate all adverse events according to the NCI
Common Terminology for Adverse Events (CTCAE), version 4.03.  
- 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.  
As the study treatment is combination regimen, the 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 investigator's opinion, there is sufficient data to support full attribution of the adverse experience to the single agent.
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8.3 adverse events and serious

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, symptoms, clinically significant laboratory abnormality,, 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 Sponsor's product, is also an adverse event.  
Progression of the cancer under study is not considered an adverse event unless it is considered to be drug related by the investigator. 8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
A serious adverse event is any adverse event occurring at any dose or during any use of Investigation product/s that:
- Results in death;  
- Is life threatening;
- Results in persistent or significant disability/incapacity;  
- Results in or prolongs an existing inpatient hospitalization; - Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug Is a new cancer (that is not a condition of the study);
- Is associated with an overdose;
- Is another important medical event
The terms "severe" and "serious" are not synonymous. Severity refers to the intensity of an adverse event (e.g., rated as mild, moderate, or severe, or according to NCI CTCAE criteria; the event itself may be of relatively minor medical significance (such as severe headache without any further findings). Severity and seriousness need to be independently assessed for each adverse event recorded on the CRF.  
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 8.3.3.1 SEVERITY OF EVENT
An investigator who is a qualified physician will evaluate all adverse events as to:
CTCAE V 4.03 Grade 1 Mild; asymptomatic or mid symptoms; clinical or diagnostic  
| observations only; intervention not indicated.   |                                                                                                                                                                          |
|--------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 2                                          | Moderate; minimal, local or noninvasive intervention indicated;  limiting age-appropriate instrumental ADL.                                                              |
| Grade 3                                          | Severe or medically significant but not immediately life-threatening;  hospitalization or prolongation or hospitalization indicated; disabling;  limiting self-care ADL. |
| Grade 4                                          | Life threatening consequences; urgent intervention indicated.                                                                                                            |
| Grade 5                                          | Death related to AE                                                                                                                                                      |
| 8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION       |                                                                                                                                                                          |  
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION
The determination of the likelihood that the study treatment caused the adverse event will be provided by an investigator who is a qualified physician. The investigator's signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame.
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8.3.3.3 assessment of causality of

Investigators should use their knowledge of the patient, the circumstances surrounding the event, and an evaluation of any potential alternative causes to determine whether or not an adverse event is considered to be related to the study treatment.  
AEs will be categorized according to the likelihood that they are related to the study drug(s). Specifically, they will be categorized using the following terms:  
| Unrelated   | The Adverse Event is not related to the drug(s)        |
|-------------|--------------------------------------------------------|
| Unlikely    | The Adverse Event is doubtfully related to the drug(s) |
| Possible    | The Adverse Event may be related to the drug(s)        |
| Probable    | The Adverse Event is likely related to the drug(s)     |
| Definite    | The Adverse Event is clearly related to the drug(s)    |
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8.3.8 adverse event reporting

For non-serious Adverse Events, documentation must begin from the time the informed consent document is signed through the 30 day follow-up period after study drug is discontinued.  
Collected information should be recorded in the electronic/Case Report Forms (eCRF/CRF) for that subject. A description of the event, its severity or toxicity grade (according to NCI's Common Toxicity Criteria (CTCAE)v.4.03), onset and resolved dates (if applicable), and the relationship to the study drug should be included. Documentation should occur in real time. The principal investigator has final responsibility for determining the attribution of the event as it is related to the study drug.
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8.3.9 serious adverse event reporting

For any experience or condition that meets the definition of a serious adverse event (SAE), recording of the event must begin after signing of the informed consent and continue through the 30 day follow-up period after treatment is discontinued.  
Given the potential risk for delayed immune-related toxicities, SAE's that are at least possibly related to study drug will be captured for 90 days after the last dose of study drug administration.  
Investigators must report to the DSMC any serious adverse events (SAE), whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64). SAEs must be reported via an OnCore SAE Report within 24 hours of learning of the event.  
An adverse event is considered **serious** if it results in ANY of the following outcomes:  
1. Death 2. A life-threatening adverse event 3. An adverse event that results in inpatient hospitalization OR prolongation of existing hospitalization for ≥ 24 hours 4. A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions 5. A congenital anomaly/birth defect.  
6. Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6).
The extended safety follow-up beyond 30 days after last avelumab administration may be performed either via a site visit or via a telephone call with subsequent site visit requested in case any concerns noted during the telephone call.
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8.3.10 reporting events to participants

All grade 4 adverse events noted among other patients in this study, or other studies with this combination will be notified to other patients enrolled in the study.  
Although pregnancy and lactation are not considered adverse events, it is the responsibility of investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported to them) that occurs during the trial or within 120 days of completing the trial or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier. All subjects who become pregnant must be followed to the completion/termination of the pregnancy.  
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events (Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported. Such events must be reported within 24 hours to the Sponsor either by electronic media or paper.
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8.4 unanticipated problems 8.4.1 definition

The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to participants or others to include, in general, any incident, experience, or outcome that meets all of the following criteria:  
- Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the participant population being studied;
- Related or possibly related to participation in the research ("possibly related" means there is a reasonable possibility that the incident, experience, or outcome may have been caused by the procedures involved in the research); and
- Suggests that the research places participants or others at a greater risk of harm (including physical, psychological, economic, or social harm) than was previously known or recognized.
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8.4.2 unanticipated problem reporting

The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board
(IRB) and to the principal investigator. The UP report will include the following information:
- Protocol identifying information: protocol title and number, PI's name, and the IRB project number;  
- A detailed description of the event, incident, experience, or outcome;
- An explanation of the basis for determining that the event, incident, experience, or outcome represents an UP;
- A description of any changes to the protocol or other corrective actions that have been taken or are proposed in response to the UP.  
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:  
- UPs that are serious adverse events (SAEs) will be reported to the IRB and to the DCC/study sponsor within 10 working days of the investigator becoming aware of the event.  
- Any other UP will be reported to the IRB and to the DCC/study sponsor within 10 working days of the investigator becoming aware of the problem.  
- All UPs should be reported to appropriate institutional officials (as required by an institution's written reporting procedures), the supporting agency head (or designee), and the Office for Human Research Protections (OHRP) within 10 working days of the IRB's receipt of the report of the problem from the investigator.
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS Not applicable
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9 statistical considerations 9.1 statistical

The combination of Avelumab and Docetaxel was not tested in urothelial cancer. Hence, it would be prudent to establish the safe dose of this combination to study in phase II and III clinical trials. We hypothesize the combination of Avelumab and Docetaxel is safe and efficacious in patients with metastatic urothelial cancer.
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primary endpoints

Phase 1b Dose De-escalation: Incidence of dose limiting toxicities (DLTs) with combination of Avelumab and Docetaxel in subjects with metastatic urothelial cancer Phase 1b Dose Expansion: Overall response rate (ORR) (complete response (CR) + partial response (PR))
per RECIST v1.1 with the established dose of combination therapy with Avelumab and Docetaxel in subjects with metastatic urothelial cancer
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secondary endpoints phase 1b dose

- Radiologic progression-free survival (PFS) per RECIST v1.1. PFS is defined as the time between the first dose of study therapy and the earliest date of confirmed progression or death. Subjects who have neither progressed nor died will be censored at the last tumor assessment date for PFS. Efficacy assessments as per section 8.  
- Overall survival (OS) defined as the time between the first dose of study therapy and death
(subjects who have not died will be censored at the most recent last-known-alive date).
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9.2 sample size determination phase

The primary objectives of the Phase 1b portion of this study are to assess the safety of and determine the recommended dose of a combination treatment of avelumab (10 mg/kg) and docetaxel for metastatic bladder cancer. This study will utilize a standard 3+3 dose de-escalation design. The dose levels to which patients will be assigned in sequential cohorts are listed below.  
| Avelumab   | Docetaxel   |          |
|------------|-------------|----------|
| Level 0    | 10 mg/kg    | 75 mg/m2 |
| Level -1   | 10 mg/kg    | 60 mg/m2 |
| Level -2   | 10 mg/kg    | 45 mg/m2 |  
An initial cohort of three patients will be treated at dose level 0. Decision of when and how to deescalate are described below.  
| Number of patients with DLT      | Decision Rule                                                                                                                                                                                                                                                    |
|----------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| at a given dose level 0 out of 3 | Enter 3 additional patients at the same dose level - If 1 or fewer of these three patients experience DLT, this dose level will be  declared the maximally administered dose. - If 2 or more experience a DLT, de-escalate to next dose level.                   |
| 1 out of 3                       | Enter up to 3 additional patients at the same dose level.  - If 0 of these 3 patients experience DLT, this dose level will be declared the  maximally administered dose. - If 1 or more of these 3 patients experience DLT, de-escalate to the next dose  level. |
| ≥2 out of 3                      | De-escalate the next dose level.                                                                                                                                                                                                                                 |  
Up to 6 patients will be treated at each dose level. If DLT meets the stopping boundaries set by the above dose algorithm at dose level 0 (for example, more than 1 out of 3 or more than 1 out of 6 patients), the next set of 3 patients will be entered at the dose level of -1. If dose level -1 meets the stopping boundaries, the next set of 3 patients will be entered at dose level -2. If dose level -2 meets the stopping boundaries, the trial will be stopped. The recommended Phase Ib dose for the expansion cohort will be defined as the highest dose level for which at most 1 out of 6 patients experience a DLT.
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phase ib expansion

The primary objective of the expansion cohort is to evaluate initial tumor response to a combination treatment of avelumab (10 mg/kg) and docetaxel at the recommended dose for metastatic bladder cancer. The overall response rate for avelumab alone in second line is approximately 18% [3]. For the combination treatment, a response rate of 33% or more is considered clinically important, whereas 18%
or below is considered uninteresting. A response is defined as a complete or partial response. To obtain preliminary information regarding the response rate and evaluate futility, sample size requirements are based on the probability of stopping early for futility under the two response rates. If the true response rate is 33%, we want to probability of stopping for futility to be less than 15% and if the true response rate is 18% we want the probability of stopping for futility to be at least 65%. The table below shows the probability of stopping for futility under the two response rates when R or fewer of the N patients has a response.  
Number of  
Patients (N)  
Rejection  
number (R)  
Probability of stopping under response  
rate of 33%  
Probability of stopping under  
response rate of 18%  
20 4 15.9% 71.5% 20 5 30.8% 86.4% 21 3 4.9% 46.2%  
21 4 12.8% 67.7%  
| 21   | 5   | 25.9%   | 83.8%   |
|------|-----|---------|---------|
| 22   | 3   | 3.8%    | 42.2%   |
| 22   | 4   | 10.2%   | 63.8%   |  
The bolded line in the table is the preferred combination of patients and responses. Twenty one (21) patients will be enrolled. If 4 or fewer patients have a response the trial will stop for futility. If 5 or more patients have a response, the treatment will be deemed worthy of further investigation in a Phase II
Trial.
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sample size/accrual rate

The Phase Ib portion of this study is expected to require a minimum of 6 and a maximum of 18 evaluable patients (if de-escalation to dose levels -1 and -2 is warranted). Patients treated in Phase Ib at the recommend dose will also be included in the Phase Ib expansion portion. Additional evaluable patients will be accrued for a total of 21 patients treated at the recommended dose. The anticipated accrual rate is 1-2 patients per month who would meet inclusion criteria.
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9.3 populations for analyses

The safety population will include all enrolled patients who receive at least 1 dose of both Avelumab and Docetaxel. The primary analysis population for the study will include the safety population with separate analyses for Phase 1 dose escalation and Phase 1b dose expansion cohort. The efficacy population will comprise all patients who receive at least 1 dose of both Avelumab and Docetaxel and who have baseline and at least 1 post-baseline imaging assessment.
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9.4 statistical analyses

This section outlines the statistical analysis strategy and procedures for the trial. If, after the trial has begun, changes are made to primary or exploratory objectives and/or hypotheses, or to the statistical methods related to those objectives and/or hypotheses, then those changes, along with an explanation as to when and why they occurred, will be listed in the Clinical Study Report (CSR) for the trial. Post hoc exploratory analyses will be clearly identified in the CSR. No imputations will be made for missing data.  
Additional details of the statistical analyses to be performed will be provided in the trial Statistical Analysis Plan.
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9.4.1 general approach

Descriptive statistics will be employed to evaluate the endpoint and analyze the data. Summary statistics for continuous variables will include mean, standard deviation, median and range. Categorical variables will be presented as frequency counts and percentages; and time-to-event variables will be summarized by Kaplan-Meier medians and survival plots. Data listings will be created to support tables and present data. The preliminary efficacy analysis will be conducted on the efficacy evaluable population and safety analysis will be performed on the safety population. SAS 9.2 or higher will be used for data analysis. The data will be tabulated and analyzed with respect to patient enrollment and disposition, demographic and baseline
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9.4.4 safety analyses

All safety data will be analyzed descriptively. Absolute and relative frequencies will be used to describe the incidence of all injection-site reactions, AEs, SAEs, deaths, and laboratory values. DLTs occurring in Phase 1 will be summarized by dose level received and presented in both tables and listings
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9.4.5 baseline descriptive statistics

Demographic and baseline characteristics will be listed by patient and summarized using the all-treated population. Descriptive summary statistics (sample size, mean, median, SD, and range, when appropriate) will be provided for the continuous variables such as age, weight, and height. Count and percentage will be reported for categorical variables such as sex, race, and ethnicity. 9.4.6 PLANNED INTERIM ANALYSES No interim efficacy analysis is planned.  
9.4.7 SUB-GROUP ANALYSES No sub-group analysis is planned.
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9.4.8 tabulation of individual participant

The investigator must maintain detailed records of all trial participants who are enrolled in the trial or who undergo screening. Source documents include, but are not limited to, patient medical records and investigator's patient trial files, as well as all test results.  
The following minimum information should be entered into the enrolled patient's source documents:
- The date the patient entered the trial and the patient number
- The trial protocol number - The date that informed consent was signed
- Evidence that the patient meets trial eligibility requirements (e.g., medical history, trial procedures, evaluations) - The dates of all trial-related patient visits
- Evidence that trial-required procedures and/or evaluations were completed - Use of any concurrent medications
- Documentation of trial medication accountability - Occurrence and status of any AEs
- The date the patient exited the trial, and a notation as to whether the patient completed the trial or was discontinued early, including the reason for discontinuation - Any deviations from the protocol
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10.1.1 informed consent process

Potential subjects will be recruited from patients seen at the Holden Comprehensive Cancer Center at University of Iowa Hospitals and Clinics who appear to be eligible for the study. A member of the research team will meet with the patient to go over the informed consent document and answer any questions they may have. Other potential treatment options, whether investigational or standard of care, will be discussed with the patient. The patient will be given the time they need to make their decision; they are encouraged to discuss it with their family and/or friends. If the patient decides to participate, they will need to sign the consent form during one of their clinic visits. No study-specific procedures will be performed before the informed consent document is signed. To avoid coercion, potential patients will be informed that they are free to refuse to participate in the trial, and that refusing to participate will not affect the availability of future medical care at UIHC. A
copy of the signed informed consent document will be given to the patient.
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10.1.2 data monitoring and management

All studies that undergo PRMC review and/or utilize HCCC Clinical Research Services (CRS) resources are required to register subjects in OnCore. Each subject registration includes the following:
- The subject's IRB approved (version date) consent form and the date of their consent. - Date of eligibility and eligibility status (eligible, not eligible)
- On study date and subject's disease site (and histology if applicable)
- On treatment date (if applicable)
All subject registration information is expected to be entered into OnCore within 2 (two) **business days**
after the subject's study visit.
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10.1.2.1 subject data

For HCCC investigator initiated trials, research staff are responsible for entering subject study data (data collection) into OnCore electronic case report forms (eCRFs). These eCRFs must be approved by the PI
and statistician prior to study activation to ensure sufficient and necessary data acquisition. All information entered into eCRFs will be traceable to the source documents which are generally maintained in the subject's file. eCRF data entry needs to be timely and should be entered into OnCore as soon as possible but no later than 14 (fourteen) business days after the subject's visit, including adverse events, tumor measurements, administration of study medication, concomitant medications, labs, and vitals. Physical exam assessments must be entered no later than 14 (fourteen) business days following completion of the physician's clinic note in the medical record. Timely data entry facilitates remote monitoring of data, allows the data to progress appropriately through the data cleaning process, and helps prevent a backlog of data queries.
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10.1.2.2 forms monitoring

OnCore eCRF data are monitored on a routine basis (dependent on accrual) to ensure all data are entered completely, accurately, and within time requirements outlined above. The assigned DSMC
monitor will coordinate and complete the data monitoring review. When the time comes to monitor a study (based on patient accrual and assigned risk level of trial) the monitor arranges for a selection of cases to be reviewed from among the subjects registered in OnCore. As part of the forms monitoring process, the assigned monitor will issue queries via OnCore (linked to the eCRF) to resolve missing, incomplete, and/or incorrect information. A member of the research team is expected to respond to these monitoring queries within 14 **(fourteen) business days.**
The monitoring process can often identify misunderstandings or deficiencies in the written, research protocol requirements earlier in the study process and thereby improve data quality and reduce rework.
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10.1.2.3 final reports

A summary of each subject's data record is continually available to the PI, research staff, and DSMC from OnCore's Biostat Console. The availability of this information is a valuable tool for the preparation of final reports and manuscripts as well as ongoing deficiency reports.
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10.2 trial-specific data and safety

10.2.1 STUDY RISK-LEVEL:
Level 1—low risk of morbidity or death, * <1% of death or any adverse event  
Level 2—risk of death* <1% or any adverse event 1% - 5% Level 3—risk of death* 1% - 5% or grade 4 - 5 ADvers 1% - 5%
Level 4—risk of death* >5% or grade 4 - 5 SAE >5%
Drugs being used on a "compassionate" basis
* Risk of death" refers specifically to 100-day treatment-related mortality 10.2.2 REPORTING AND MONITORING REQUIREMENTS:
All institutional investigator initiated trials (IITs), regardless of assigned risk level are subject to routine DSMC monitoring activities which may include but are not limited to review of signed consent documents, eligibility and adverse event reporting.  
All institutional IITs have the following **reporting requirements** as part of their DSMP:
- Register all subjects in HCCC's Clinical Trial Management System, OnCore
- Document Adverse Events
- Document protocol deviations
- Provide an annual progress report to the DSMC via OnCore data export 10.2.3 SELECTED MONITORING STRATEGY BASED ON RISK-LEVEL:
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10.2.3.1 risk level 4

Interventional treatment trials involving investigational agents or devices with a risk of death* (>5% or grade 4 - 5 SAE >5%), e.g. all investigator initiated INDs, most Phase I/II trials, gene therapy, gene manipulation or viral vector systems high-risk clinical procedures if performed solely for research purposes. The use of a new chemical or drug for which there is limited or no available safety data in humans.
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10.2.3.2 study safety review

An independent study monitor and/or the DSMC Chair (or designee), will review study data (provided by the PI/available in OnCore) and communicate with the PI at least biannually. A copy of this communication will be forwarded to the DSMC and PRMC Chairs.
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10.2.4 additional reporting requirements

- A scanned copy of the completed eligibility checklist, with screening information and PI
signature, will be attached in OnCore for ongoing review by DSMC staff.  
- Serious adverse events will be entered directly into an OnCore SAE report by the research team.  
OnCore will send an automatic notification to the DSMC Chair/acting Chair and staff for review.
- The DSMC utilizes a risk-based monitoring approach. The trial's research records will be monitored at minimum twice per year. Monitoring may be done more frequently depending on the protocol, risks to subjects, reported serious/adverse events, patient population and accrual rate. Records for a minimum of 25% of subjects will be monitored for the entire study.  
Monitoring will involve the following:  
- review eligibility of patients accrued to the study,
- check for the presence of a signed informed consent,
- determine compliance with protocol's study plan, - determine whether SAEs are being appropriately reported to internal and external regulatory agencies,
- compare accuracy of data in the research record with the primary source documents,
- review investigational drug processing and documentation, - Assess cumulative AE/SAE reports for trends and compare to study stopping rules. - "IND safety report" for 15-day reports, or
- "7-day IND safety report" for unexpected fatal or life-threatening suspected adverse reaction reports, or
- "Follow-up IND safety report" for follow-up information.  
- Treatment regimen (dosing frequency, combination therapy)
- Protocol description (and number, if assigned)
- Description of event, severity, treatment, and outcome, if known (grading the event per CTCAE) - Supportive laboratory results and diagnostics
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fda reporting requirements (for sponsor-investigators)

It is the responsibility of the IND sponsor-investigator to comply with IND safety reporting as set forth in the Code of Federal Regulations, Section 312.32. This responsibility includes providing an annual IND
report to the FDA. All IND safety reports must be submitted on Form 3500A and be accompanied by Form 1571. The type of report (initial or follow-up) should be checked in the respective boxes on Forms 3500A and 1571. See Instructions for completing Form 3500A. Please note all instance of UIHC, location, and faculty / staff should be redacted from supporting documentation and the 3500A.  
The submission must be identified as: For detailed explanation of the above definitions, requirements, and procedures related to IND application safety reports and the responsibilities of IND applications sponsors with regard to such reporting, refer to Guidance for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE Studies (PDF - 227KB)
In addition to completing appropriate patient demographic and suspect medication information, the report should include the following information within the Event Description (section 5) of the MedWatch 3500A form:  
- Sponsor-Investigator's assessment of the relationship of the adverse event to each investigational product and suspect medication
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11 references

1. Sharma, P., et al., *Nivolumab monotherapy in recurrent metastatic urothelial carcinoma*
(CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol, 2016. 17(11): p. 1590-1598.  
2. Bellmunt, J., et al., *Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma.*
New England Journal of Medicine, 2017. 376(11): p. 1015-1026.  
3. Apolo, A.B., et al., Avelumab, an Anti-Programmed Death-Ligand 1 Antibody, In Patients With Refractory Metastatic Urothelial Carcinoma: Results From a Multicenter, Phase Ib Study. J Clin Oncol, 2017. 35(19): p. 2117-2124.  
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