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10.2.2.4 immune-related adverse events

Since inhibition of PD-L1 stimulates the immune system, immune-related AEs (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 Table 2 Management of Immune-mediated Adverse Reactions: Guidance in this table is relevant to toxicities probably related to Avelumab. For toxicity attributed to trabectedin, treat according to the protocol or standard of care if treatment is not otherwise specified.  
| Gastrointestinal irAEs Severity of Diarrhea / Colitis (NCI-CTCAE v4)                                                                                                                                                                                          | Management                                                                                                                                                                                 | Follow-up                                                                                                                                                   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1 Diarrhea: < 4 stools/day over Baseline Colitis: asymptomatic                                                                                                                                                                                          | Continue avelumab therapy                                                                                                                                                                  | Close monitoring for worsening symptoms                                                                                                                     |
| Symptomatic treatment (e.g. loperamide)                                                                                                                                                                                                                       | Educate subject to report worsening immediately If worsens: Treat as Grade 2, 3 or 4.                                                                                                      |                                                                                                                                                             |
| Grade 2  Diarrhea: 4 to 6 stools per day over Baseline;  IV fluids indicated < 24 hours; not interfering  with ADL Colitis: abdominal pain; blood in stool                                                                                                    | Withhold avelumab therapy                                                                                                                                                                  | If improves to Grade ≤ 1: Resume avelumab therapy                                                                                                           |
| Symptomatic treatment                                                                                                                                                                                                                                         | If persists > 5-7 days or recurs: Treat as Grade 3 or 4.                                                                                                                                   |                                                                                                                                                             |
| Grade 3 to 4 Diarrhea (Grade 3): ≥ 7 stools per day over  Baseline; incontinence; IV fluids ≥ 24 h;  interfering with ADL Colitis (Grade 3): severe abdominal pain,  medical intervention indicated, peritoneal  signs Grade 4: life-threatening, perforation | Withhold avelumab for Grade 3. Permanently  discontinue avelumab for Grade 4 or recurrent Grade 3.                                                                                         | If improves: Continue steroids until Grade ≤ 1, then taper  over at least 1 month; resume avelumab therapy  following steroids taper (for initial Grade 3). |
| 1.0 to 2.0 mg/kg/day prednisone IV or equivalent Add prophylactic antibiotics for opportunistic infections.  Consider lower endoscopy.                                                                                                                        | If worsens, persists > 3 to 5 days, or recurs after  improvement: Add infliximab 5mg/kg (if no  contraindication). Note: infliximab should not be used in  cases of perforation or sepsis. |                                                                                                                                                             |  
| Dermatological irAEs Grade of Rash (NCI-CTCAE v4)                                                                                                      | Management                                                                               | Follow-up                                                                                                                                                                                                                                                                                              |
|--------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1 to 2                                                                                                                                           | Continue avelumab therapy Symptomatic therapy (for                                       | If persists > 1 to 2 weeks or recurs: Withhold avelumab                                                                                                                                                                                                                                                |
| Covering ≤ 30% body surface area                                                                                                                       | example, antihistamines, topical steroids)                                               | therapy. Consider skin biopsy. Consider 0.5-1.0  mg/kg/day prednisone or equivalent. Once improving,  taper steroids over at least 1 month, consider  prophylactic antibiotics for opportunistic infections, and  resume avelumab therapy following steroids taper. If worsens: Treat as Grade 3 to 4. |
| Grade 3 to 4 Grade 3: Covering > 30% body surface area;  Grade 4: Life threatening consequences                                                        | Withhold avelumab for Grade 3.Permanently discontinue  for Grade 4 or recurrent Grade 3. | If improves to Grade ≤ 1:  Taper steroids over at least 1 month; resume avelumab  therapy following steroids taper (for initial Grade 3).                                                                                                                                                              |
| Consider skin biopsy, Dermatology consult, 1.0 to 2.0  mg/kg/day prednisone or equivalent. Add prophylactic  antibiotics for opportunistic infections. |                                                                                          |                                                                                                                                                                                                                                                                                                        |  
| 9717 / RG9217009 Pulmonary irAEs Grade of Pneumonitis (NCI-CTCAE v4)                         | Management                                                                                                                                                                                                                                         | Follow-up                                                                                                                                                                                                                                                                       |
|----------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1                                                                                      | Consider withholding avelumab therapy. Monitor for                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                 |
| Radiographic changes only                                                                    | symptoms every 2 to 3 days. Consider Pulmonary and  Infectious Disease consults.                                                                                                                                                                   | Re-assess at least every 3 weeks If worsens: Treat as Grade 2 or Grade 3 to 4.                                                                                                                                                                                                  |
| Grade 2                                                                                      | Withhold avelumab therapy. Pulmonary and Infectious                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                 |
| Mild to moderate new symptoms                                                                | Disease consults. Monitor symptoms daily; consider  hospitalization. 1.0 to 2.0 mg/kg/day prednisone or  equivalent. Add prophylactic antibiotics for opportunistic  infections. Consider bronchoscopy, lung biopsy .                              | Re-assess every 1 to 3 days.  If improves: When symptoms return to Grade ≤ 1, taper  steroids over at least 1 month, and then resume  avelumab therapy following steroids taper.  If not improving after 2 weeks or worsening or for  recurrent Grade 2: Treat as Grade 3 to 4. |
| Grade 3 to 4 Grade 3: Severe new symptoms;  New/worsening hypoxia; Grade 4: Life-threatening | Permanently discontinue avelumab therapy. Hospitalize. Pulmonary and Infectious Disease consults. 1.0 to 2.0  mg/kg/day prednisone or equivalent. Add prophylactic  antibiotics for opportunistic infections. Consider  bronchoscopy, lung biopsy. | If improves to Grade ≤ 1: Taper steroids over at least 1  month  If not improving after 48 hours or worsening: Add  additional immunosuppression (for example, infliximab,  cyclophosphamide, IV immunoglobulin, or  mycophenolate mofetil)                                     |  
| 9717 / RG9217009 Hepatic irAEs Grade of Liver Test Elevation (NCI-CTCAE v4)                                                                                                       | Management                                                                                                                                                                                                                                                                                                                                  | Follow-up                                                                                                                                                                                                                                                                                             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Grade 1 Grade 1 AST or ALT > ULN to 3.0 x ULN and/or  Total bilirubin > ULN to 1.5 x ULN                                                                                          | Continue avelumab therapy.                                                                                                                                                                                                                                                                                                                  | Continue liver function monitoring  If worsens: Treat as Grade 2 or 3 to 4.                                                                                                                                                                                                                           |
| Grade 2  AST or ALT > 3.0 to ≤ 5 x ULN and / or total  bilirubin > 1.5 to ≤ 3 x ULN (this is common for  trabectedin) Withhold avelumab therapy. Increase frequency of monitoring | If returns to Grade ≤ 1 or Baseline: Resume                                                                                                                                                                                                                                                                                                 |                                                                                                                                                                                                                                                                                                       |
| to every 3 days.                                                                                                                                                                  | routine monitoring; resume avelumab therapy. If elevation persists > 5 to 7 days or worsens: Treat as Grade 3 to 4.                                                                                                                                                                                                                         |                                                                                                                                                                                                                                                                                                       |
| Grade 3 to 4 AST or ALT > 5 x ULN and / or total bilirubin >  3 x ULN                                                                                                             | Permanently discontinue avelumab therapy. Increase frequency  of monitoring to every 1 to 2 days. 1.0 to 2.0 mg/kg/day  prednisone or equivalent. Add prophylactic antibiotics for  opportunistic infections. Consult gastroenterologist/  hepatologist. Consider obtaining MRI/CT scan of liver and liver  biopsy if clinically warranted. | If returns to Grade ≤ 1 or baseline: Taper steroids  over at least 1 month  If does not improve in > 3 to 5 days, worsens or  rebounds: Add mycophenolate mofetil 1 gram (g)  twice daily. If no response within an additional 3 to  5 days, consider other immunosuppressants per  local guidelines. |  
| 9717 / RG9217009 Endocrine irAEs Endocrine Disorder                                                                                                                                                                                                                                                                                                                          | Management                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Follow-up                                                                                        |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------|
| Grade 1 or Grade 2 endocrinopathies  (hypothyroidism, hyperthyroidism, adrenal  insufficiency, type I diabetes mellitus)                                                                                                                                                                                                                                                     | Continue avelumab therapy. Endocrinology consult if needed.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | Continue hormone  replacement/suppression and  monitoring of endocrine function as  appropriate. |
| Start thyroid hormone replacement therapy (for hypothyroidism),  anti-thyroid treatment (for hyperthyroidism), corticosteroids (for adrenal  insufficiency) or insulin (for Type I diabetes mellitus) as appropriate.  Rule-out secondary endocrinopathies (i.e. hypopituitarism / hypophysitis) Withhold avelumab therapy. Consider hospitalization. Endocrinology consult. | Resume avelumab once symptoms  and/or laboratory tests improve to  Grade ≤ 1 (with or without hormone  replacement/suppression).                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |                                                                                                  |
| Grade 3 or Grade 4 endocrinopathies  (hypothyroidism, hyperthyroidism, adrenal  insufficiency, type I diabetes mellitus)                                                                                                                                                                                                                                                     | Start thyroid hormone replacement therapy (for hypothyroidism),  anti-thyroid treatment (for hyperthyroidism), corticosteroids (for adrenal  insufficiency) or insulin (for type I diabetes mellitus) as appropriate.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Continue hormone  replacement/suppression and  monitoring of endocrine function as  appropriate. |
| Rule-out secondary endocrinopathies (i.e. hypopituitarism / hypophysitis)                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      |                                                                                                  |
| Hypopituitarism/Hypophysitis (secondary                                                                                                                                                                                                                                                                                                                                      | If secondary thyroid and/or adrenal insufficiency is confirmed (i.e.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 |                                                                                                  |
| endocrinopathies)                                                                                                                                                                                                                                                                                                                                                            | subnormal serum FT4 with inappropriately low TSH and/or low serum  cortisol with inappropriately low ACTH) : Refer to endocrinologist for dynamic testing as indicated and  measurement of other hormones (FSH, LH, GH/IGF-1, PRL, testosterone in  men, estrogens in women). Hormone replacement/suppressive therapy  as appropriate. Perform pituitary MRI and visual field examination as  indicated.  Resume avelumab once symptoms and  hormone tests improve to Grade ≤ 1  (with or without hormone replacement). In addition, for hypophysitis with  abnormal MRI, resume avelumab only  once shrinkage of the pituitary gland on  MRI/CT scan is documented.  If hypophysitis confirmed: Continue avelumab if mild symptoms with normal MRI. Repeat the MRI in  1 month. Withhold avelumab if moderate, severe or life-threatening  symptoms of hypophysitis and/or abnormal MRI. Consider hospitalization.  Initiate corticosteroids (1 to 2 mg/kg/day prednisone or equivalent)  followed by corticosteroids taper during at least 1 month. Add  prophylactic antibiotics for opportunistic infections. Continue hormone  replacement/suppression therapy as  appropriate. |                                                                                                  |  
| Renal irAEs Grade of Creatinine Increased (NCI-CTCAE v4) Initial Management   | Follow-up Management                                                                                                                                                                                                                                                                                                           |                                                                           |
|-------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------|
| Grade 1                                                                       | Continue avelumab therapy.                                                                                                                                                                                                                                                                                                     | Continue renal function monitoring.                                       |
| Creatinine increased > ULN to 1.5 x ULN                                       | If worsens: Treat as Grade 2 to 3 or 4.                                                                                                                                                                                                                                                                                        |                                                                           |
| Grade 2 to 3                                                                  | Withhold avelumab therapy. Increase frequency of                                                                                                                                                                                                                                                                               |                                                                           |
| Creatinine increased > 1.5 and ≤ 6 x ULN                                      | monitoring to every 3 days. 1.0 to 2.0 mg/kg/day  prednisone or equivalent. Add prophylactic antibiotics for  opportunistic infections. Consider renal biopsy. If returns to Grade ≤1 or baseline: Taper steroids over at least 1 month, and resume  avelumab therapy following steroids taper. If worsens:  Treat as Grade 4. |                                                                           |
| Grade 4                                                                       | Permanently discontinue avelumab therapy. Monitor                                                                                                                                                                                                                                                                              |                                                                           |
| Creatinine increased > 6 x ULN                                                | creatinine daily. 1.0 to 2.0 mg/kg/day prednisone or  equivalent. Add prophylactic antibiotics for opportunistic  infections. Consider renal biopsy. Nephrology consult.                                                                                                                                                       | If returns to Grade ≤1 or baseline: Taper steroids over at least 1 month. |  
| Cardiac irAEs Myocarditis                                                                                                                                                                                                                                        | Management                                                                                                                                                                                                                                                                                                                                                     | Follow-up                                                                                                                                                                                                                                                                                   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| New onset of cardiac signs or symptoms and /  or new laboratory cardiac biomarker  elevations (e.g. troponin, CK-MB, BNP) or  cardiac imaging abnormalities suggestive of  myocarditis.                                                                          | Withhold avelumab therapy. Hospitalize. In the presence  of life threatening cardiac decompensation, consider  transfer to a facility experienced in advanced heart  failure and arrhythmia management. Cardiology consult  to establish etiology and rule-out immune-mediated  myocarditis. Guideline based supportive treatment as  per cardiology consult.* | If symptoms improve and immune-mediated etiology is  ruled out, re-start avelumab therapy. If symptoms do not improve/worsen, viral myocarditis is  excluded, and immune-mediated etiology is suspected or  confirmed following cardiology consult, manage as  immune-mediated myocarditis. |
| Consider myocardial biopsy if recommended per  cardiology consult.                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                             |
| Immune-mediated myocarditis                                                                                                                                                                                                                                      | Permanently discontinue avelumab. Guideline based  supportive treatment as appropriate as per cardiology  consult.* 1.0 to 2.0 mg/kg/day prednisone or equivalent. Add prophylactic antibiotics for opportunistic infections.                                                                                                                                  | Once improving, taper steroids over at least 1 month. If no improvement or worsening, consider additional  immunosuppressants (e.g. azathioprine, cyclosporine A).                                                                                                                          |
| *Local guidelines, or eg. ESC or AHA guidelines  ESC guidelines website: https://www.escardio.org/Guidelines/Clinical-Practice-Guidelines AHA guidelines website: http://professional.heart.org/professional/GuidelinesStatements/searchresults.jsp?q=&y=&t=1001 |                                                                                                                                                                                                                                                                                                                                                                |                                                                                                                                                                                                                                                                                             |  
| 9717 / RG9217009 Other irAEs (not described above) Grade of other irAEs                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Initial Management   | Follow-up Management   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------|------------------------|
| (NCI-CTCAE v4) Grade 2 or Grade 3 clinical signs or symptoms  Withhold avelumab therapy pending clinical investigation. If irAE is ruled out, manage as appropriate according to the  suggestive of a potential irAE diagnosis and consider re-starting avelumab therapy If irAE is confirmed, treat as Grade 2 or 3 irAE. Grade 2 irAE or first occurrence of Grade 3  Withhold avelumab therapy. 1.0 to 2.0 mg/kg/day  irAE prednisone or equivalent. Add prophylactic antibiotics for  opportunistic infections. Specialty consult as appropriate. If improves to Grade ≤ 1 or baseline: Taper steroids over  at least 1 month and resume avelumab therapy following  steroids taper. Recurrence of same Grade 3 irAEs Permanently discontinue avelumab therapy. Up to 2.0  mg/kg/day prednisone or equivalent. Add prophylactic  antibiotics for opportunistic infections. Specialty consult as  appropriate. If improves to Grade ≤ 1 or baseline: Taper steroids over at  least 1 month. Grade 4 Permanently discontinue avelumab therapy. Up to 2.0  mg/kg/day prednisone or equivalent and/or other  immunosuppressant as needed. Add prophylactic  antibiotics for opportunistic infections. Specialty consult. If improves to Grade ≤ 1 or baseline: Taper steroids over  at least 1 month Requirement for 10 mg per day or greater  prednisone or equivalent for more than 12  weeks for reasons other than hormonal  replacement for adrenal insufficiency Permanently discontinue avelumab therapy. Specialty  consult. Persistent Grade 2 or 3 irAE lasting 12 weeks  or longer |                      |                        |  
**Grade 2 hepatic toxicity is common with trabectedin and grade 3 can happen occasionally. While it is necessary to include these treatment guidelines for safety, in reality it is more likely that hepatic toxicity will be related to trabectedin.
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10.3 toxicity of trabectedin

Trabectedin is given as standard of care and does have notable toxicities. The following are to be considered expected toxicities of trabectedin:  
- Leukopenia (with neutropenia as the predominant component) - Malaise - Infection/sepsis - Transaminase Elevation - CK elevation - Bilirubin or Alkaline phosphatase elevation - Fatigue - Nausea/vomiting - Renal toxicity
Rhabdomyolysis is an unusual but well-described toxicity of trabectedin. If rhabdomyolysis is observed in a single case, this should not be considered a DLT but if multiple cases are seen, this must be reviewed by the DSMB.
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10.4 dose modification of trabectedin

Trabectedin is to be started at 1.5 mg/m2. After the first week, the dose may be reduced if clinically indicated for toxicity management. Dose reductions will be noted in the subject's clinical record or research shadow chart.  
As per standard practice, the subjects first dose reduction will be to 1.2 mg/m2 and the second dose reduction will be to 1 mg/m2. Dose reductions beyond 1 mg/m2 are not permitted. If a subject is unable to tolerate a dose of 1mg/m2, they must come off study. Trabectedin may be spaced out initially to 4 weeks and then to 5 weeks, as needed for toxicity management. If, in the opinion of the treating investigator, trabectedin needs to be spaced out greater than 5 weeks, Sponsor-Investigator approval is required.  
Trabectedin dose reduction is required for the following adverse reactions:
- ANC < 1000/μL with fever and infection - ANC <500/μL lasting > 5 days - Platelets < 25,000/ μL
- Grade 3 or higher nausea and vomiting that persists despite a full anti-emetic regimen
- Grade 3 transaminitis not recovering to <2.5 x ULN or subject's baseline by 3 weeks post infusion - Grade 3 Alk Phos Elevation not recovering to <2.5 x ULN or subject's baseline by 3 weeks post-infusion - Total Bilirubin > 2.5 x ULN (direct bilirubin can be used if there is suspicion for Gilbert's syndrome) - CK > 2.5 x ULN - EF <45%
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11.0 subject discontinuation of active

Subjects may be removed from this study at any time at their discretion. Subjects may also be removed from this protocol if they develop any untoward side effects from the study medications.  
If a subject withdraws consent to participate in the study or aspects of the study, attempts should be made to obtain permission to record survival data up to the protocol-described end of the subject follow-up period. Documentation in the medical record Subjects receiving the 1mg/m2 dose of trabectedin with liver involvement from their cancer or baseline liver dysfunction, who are otherwise tolerating treatment well and appear to be benefiting from treatment on the study, may continue at the 1mg/m2 after recovery from their liver dysfunction to grade 2, with Sponsor-Investigator approval.  
or source should state that the subject is withdrawing from the study and what, if any, selected data the subject will permit the investigator to obtain.  
An explanation for discontinuing treatment is recorded for each subject discontinuing treatment In the subject's medical record or research shadow chart. The Sponsor-Investigator must be notified immediately if a subject discontinues treatment. All subjects, irrespective of treatment status, will continue to be followed for survival. Treatment in this study must be discontinued for any of the following reasons:  
- if the Sponsor-Investigator decides to stop the study; - at Investigator's discretion; - at the subject's request;
- if the subject enrolls in a trial of another investigational agent; - Grade 4 or life-threatening toxicity (See Section 9, Adverse Events) attributable to study agent, unless otherwise addressed;
- progression;
- pregnancy.
A subject that enters hospice care will be considered withdrawn from the study. Adverse events will no longer be monitored or recorded. If the subject experiences a serious adverse event related to study treatment prior to withdrawal, this event will be followed to resolution or recovered with sequelae. Subjects and their families will no longer be contacted, however survival status may be obtained via electronic medical record or public database.
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12.0 concomitant medications

All medications taken at the start of the study will be documented/recorded in in the subject's medical record or research shadow chart.
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12.1 pre-medication treatment with trabectedin

Pre-medication: Subjects will receive avelumab by IV infusion following pretreatment with H1 blockers and acetaminophen once every 2 weeks. Premedication with an antihistamine and with paracetamol (acetaminophen) (for example, 25-50 mg diphenhydramine and 500-650 mg paracetamol [acetaminophen] IV or oral equivalent) 30 to 60 minutes prior to the first four (4)
doses of avelumab. Premedication may be discontinued for Cycle 5 and beyond of avelumab, at the investigator's discretion. This regimen may be modified based on local treatment standards and guidelines as appropriate provided it does not include systemic corticosteroids.  
Likewise, trabectedin is a moderately emetogenic chemotherapy and anti-emetics should be given according to standard of care including 20 mg dexamethasone IV given at 20-30 minutes before trabectedin. Alterations to the dexamethasone route of administration may be allowed with Sponsor-Investigator approval. Outside of this pre-medication recommended in the trabectedin package insert, corticosteroids use is discouraged when not absolutely necessary and is not allowed for the treatment of trabectedin associated nausea and vomiting unless the subject has tried and failed to control their nausea with 2 prior antiemetic regimens. Additional information regarding premedication and administration schedule is noted in Section 7.0.
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12.2 cyp3a4 inhibitors and inducers

It is notable that trabectedin is metabolized through CYP3A4. All inhibitors or inducers of cytochrome CYP3A4 (see below) should be noted prior to study entry.  
Inhibitors of CYP3A4 include but are not limited to:
- aprepitant - clarithromycin - clotrimazole  
- diltiazem - erythromycin - fluconazole - grapefruit juice - indinavir
- itraconazole
- ketoconazole - nefazodone - nelfinavir - ritonavir - saquinavir - telithromycin - troleandomycin
- verapamil
Should a subject start on any of these drugs, dose modifications of trabectedin may be considered in consultation with the pharmacy and at the discretion of the subjects treating physician.  
Inactivated vaccines, including inactivated flu vaccines, are allowed on study. All other vaccinations that include live-virus components are prohibited for subjects on while on study.
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13.0 contraception

Avelumab may have adverse effects on a fetus in utero. Furthermore, it is not known if avelumab has transient adverse effects on the composition of sperm.  
Contraception guidance and definitions are provided in Appendix E.
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14.0 data and safety monitoring

Institutional support of trial monitoring will be in accordance with the FHCRC/University of Washington Cancer Consortium Institutional Data and Safety Monitoring Plan. Under the provisions of this plan, FHCRC Clinical Research Support (CRS) coordinates data and compliance monitoring conducted by consultants, contract research organizations, or FHCRC employees unaffiliated with the conduct of the study. Independent monitoring visits occur at specified intervals determined by the assessed risk level of the study and the findings of previous visits per the institutional DSMP.  
In addition, protocols are reviewed at least annually and as needed by the Consortium Data and Safety Monitoring Committee
(DSMC), FHCRC Scientific Review Committee (SRC) and the FHCRC/University of Washington Cancer Consortium Institutional Review Board (IRB). The review committees evaluate accrual, adverse events, stopping rules, and adherence to the applicable data and safety monitoring plan for studies actively enrolling or treating subjects. The IRB reviews the study progress and safety Inducers of CYP3A4 include but are not limited to:
- barbiturates - phenytoin - carbamazepine - rifabutin - rifampin
- St. John's Wort information to assess continued acceptability of the risk-benefit ratio for human subjects. Approval of committees as applicable is necessary to continue the study. The trial will comply with the standard guidelines set forth by these regulatory committees and other institutional, state and federal guidelines.
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15.0 data management/confidentiality

The investigator will ensure that data collected conform to all established guidelines. Each subject is assigned a unique subject number to protect subject confidentiality. Subjects will not be referred to by this number, by name, or by any other individual identifier in any publication or external presentation. The licensed medical records department, affiliated with the institution where the subject receives medical care, maintains all original inpatient and outpatient chart documents. Subject research files are stored in a secure place (or database). Access is restricted to authorized personnel.
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15.1 data quality assurance

Accurate and reliable data collection will be ensured by verification and crosscheck of the eCRFs against the investigator's records by the study monitor (source document verification) and by the maintenance of a drug–dispensing log by the investigator.
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15.2 data documents

The investigator must ensure that the records and documents pertaining to the conduct of the study and the distribution of the investigational product are complete, accurate, filed, and retained. Examples of source documents include: hospital records; clinic and office charts; laboratory notes; memoranda; checklists; dispensing records; recorded data from automated instruments; copies or transcriptions certified after verification as being accurate copies; microfiche; x-ray film and reports; and records kept at the pharmacy; and the laboratories, as well as copies of CRFs or CD-ROM.
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15.3 data management

Data will be collected and entered into the eCRF. These data will be electronically verified through use of programmed edit checks specified by the clinical team. Discrepancies in the data will be brought to the attention of the clinical team, and investigational site personnel, if necessary. Resolutions to these issues will be reflected in the database. An audit trail within the system will track all changes made to the data.
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15.4 investigator responsibilities for data

The investigator is responsible for complying with the requirements for all assessments and data collection (including subjects not receiving protocol-required therapies) as stipulated in the protocol for each subject in the study. For subjects who withdraw prior to completion of all protocol-required visits and are unable or unwilling to continue the Schedule of Assessments (in Appendix B, the investigator can search publicly available records (where permitted) to ascertain survival status.  
This ensures that the data set(s) produced as an outcome of the study is/are as comprehensive as possible.
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16.0 statistical considerations 16.1 study

The first six subjects (may expand up to 18) treated with avelumab combined with trabectedin will constitute the Phase 1 portion of the trial. If the combination is safe, the trial will be expanded to treat an additional 16 subjects. If a dose reduction is required based on 2 out of 6 subjects in the first phase having DLT, a dose reduction will be made, first to 1.0 mg/m2 and if <2 subjects have DLTs at that dose, re-escalated to 1.2 mg/m2. An additional 16 Phase 2 subjects will accrue using the highest dose tolerated with
<2 DLTs.  
A data and safety monitoring board will review any dose limiting toxicities that should arise on the Phase I portion of the trial. The DSMB will also review any DLTs in the extension portion of the trial at meetings described in the DSMB Charter. Should more than 30% of subjects have DLTs, accrual will halt until the DSMB can meet to advise on whether the trial may resume, with or without modification. Subjects on the Phase I portion of the study will also be included in the efficacy analysis.
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16.2 phase i design

The primary objective of the Phase I component of this study is to evaluate the safety of avelumab given in combination with trabectedin among subjects with advanced L-type sarcomas. The phase I component of this study will treat 6 subjects (modified 3+3 design) to demonstrate safety of the combination. Dose-limiting toxicities will be defined as unexpected, probably-related toxicities of grade 3 or higher.  
The study design is as follows:
6 subjects will be treated initially.  
- If 2 or more subjects experience a DLT at any point during the Phase 1 portion, a new cohort will be added, enrolling an additional 6 subjects at a reduced dose of 1 mg/m2 trabectedin.  
- Should 2 or more of these next 6 subjects at the reduced dose have a DLT, stop and convene DSMB meeting to recommend changes to the protocol.  
- If at any time in the study (including those above) 30% of subjects have a DLT, have a DSMB meeting to review specific toxicities. We will re-calculate the percent of subjects who have had a DLT each time there is a new DLT.
If <2 subjects have DLTs on the 1 mg/m2 dose level, another Phase I cohort of 6 subjects implemented, re-escalating to 1.2 mg/m2 dosing of trabectedin. If <2 DLTs are seen there, that will be the recommended Phase II dose. If 2 or greater DLTs are seen there, the Phase 2 will move forward at the 1.0 mg/m2 dose level, after discussion with the DSMB.  
Safety analysis will continue through the entire trial, if at any point during the trial 30% of subjects experience a DLT, the trial should halt and convene a meeting of the DSMB. A total of up to 18 subjects may enroll on Phase 1, and an additional 16 on Phase 2.
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16.3 phase ii design

The primary objective of the Phase II portion is to compare the objective response rate (ORR) with historical rates for single agent trabectedin. Subjects from the Phase I portion of the trial who are treated at the dose ultimately used in the expansion will be included in the efficacy analysis. Our null hypothesis estimates the overall response rate of single agent trabectedin at 9.9%. We believe an increase in the response rate to 35% would be highly compelling. A total subject number of 22 gives us an 85% power to detect this increased response rate assuming a two-sided alpha of 0.05. 6 or more subjects with responses would suggest clinical activity of this regimen over single agent trabectedin.
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16.4 data and safety monitoring

A DSMB will make recommendations to the Sponsor-Investigator should significant toxicity be observed. The DSMB will meet if 2 of the first 6 subjects have a DLT or at any point after that if more than 30% of subjects have a DLT at the 1.5, 1.2 or 1 mg/m2 dose. The DSMB will otherwise meet every 6 months while the study is actively enrolling and has active subjects on trial.  
If the trial is closed to enrollment and all subjects on study are in follow-up, the DSMB will meet once a year.
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16.5 additional efficacy hypotheses

The study is not powered to detect specific hypotheses with regards to correlative endpoints, rather this data and analysis will help better identify subjects having the potential to benefit from this therapy and aid in designing larger Phase III studies.  
Summary statistics will be used to for describing changes across time. In addition, the time course of biomarker outcomes will be investigated graphically by summary plots or individual subject plots. Peripheral blood will be analyzed to examine the impact of T cell subpopulations and investigational work using formalin fixed tumor samples for immunohistochemistry and molecular analysis; this work will be exploratory. Categorical data analysis and logistic regression will be used to evaluate the associations between correlative measures and clinical outcome (eg, response, clinical benefit, time to progression, progressionfree survival, and survival). If there is suggestion of meaningful trend, methods such as linear mixed models may be used to characterize the pattern of change over time. Kaplan-Meier methodology and Cox Proportional Hazards models will be used to evaluate time to event endpoints.
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16.6 ethnic and gender distribution

Projected Target Accrual  
| TARGETED / PLANNED ENROLLMENT: Number of Subjects Ethnic Category Sex / Gender Females   | Males   | Total   |    |
|------------------------------------------------------------------------------------------|---------|---------|----|
| Hispanic or Latino                                                                       | 4       | 4       | 8  |
| Not Hispanic or Latino                                                                   | 13      | 13      | 26 |
| Ethnic Category Total of All Subjects*                                                   | 17      | 17      | 34 |
| Racial Categories American Indian / Alaska Native                                        | 1       | 1       | 2  |
| Asian                                                                                    | 3       | 3       | 6  |
| Native Hawaiian or Other Pacific Islander                                                | 1       | 1       | 2  |
| Black or African American                                                                | 2       | 2       | 4  |
| White                                                                                    | 8       | 8       | 16 |
| More Than One Race                                                                       | 2       | 2       | 4  |
| Racial Categories: Total of All Subjects*                                                | 17      | 17      | 34 |  
17.0 **INVESTIGATOR OBLIGATIONS** The Sponsor-Investigator is responsible for the conduct of the clinical trial at the site and is responsible for personally overseeing the evaluation of all study subjects. The Sponsor-Investigator must assure that all study site personnel, including sub-Investigators and other study staff members, adhere to the study protocol and to all applicable regulations and guidelines regarding clinical trials both during and after study completion.  
All subjects are informed of the nature of the program, its possible hazards, and their right to withdraw at any time, and each subject signs a form indicating their consent to participate prior to receiving any study-related procedures.
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18.0 administrative and regulatory considerations

The Sponsor-Investigator is responsible for ensuring that all staff involved in the study are well acquainted with the protocol, study procedures, record keeping and administrative requirements, AE reporting, Good Clinical Practice guidelines, CRF/eCRF completion guidelines, monitoring requirements, and the ability of the site to satisfactorily complete the protocol. Additional documents with instructions for study compliance and CRF/eCRF completion will be provided.
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18.2 documentation

The documentation of clinical data must be stored by the Sponsor-Investigator according to legal requirements. The SponsorInvestigator and study staff has responsibility for maintaining a comprehensive and centralized filing system containing all studyrelated documentation. These files must be suitable for inspection by the Sponsor-Investigator, the FDA, and/or other applicable regulatory agencies/competent authorities at any time, and should consist of the following elements: subject files (complete medical records, laboratory data, supporting source documentation, and the Informed Consent); study files (the protocol with all amendments, copies of all pre-study documentation, and all correspondence between the Competent Authorities, IRB/EC, site, and Sponsor-Investigator); and drug accountability files, containing a complete account of the receipt and disposition of the study drug.
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18.3 data collection

Electronic case report forms must be completed and submitted for each subject enrolled in the study. Any changes or corrections made to the CRF/eCRF must be subsequently reviewed and signed by the Sponsor-Investigator. All data fields in the CRF/eCRF
must be completed to avoid queries.
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18.4 protocol interpretation and compliance

The procedures defined in the protocol are carefully reviewed by the Sponsor-Investigator and his/her staff prior to the time of study initiation to ensure accurate representation and implementation. Protocol amendments, if any, are reviewed and implemented promptly following IRB/EC approval. The Sponsor-Investigator is responsible for submitting protocol amendments to the FDA as described in 21 CFR § 312.30 (Protocol Amendments) and other regulatory agencies according to national, state or local requirements. The Sponsor-Investigator, or its designee, is always available to answer protocol- or subject-related questions.
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18.5 study monitoring and data

A study monitor may be used to ensure adherence to the protocol, applicable FDA regulations and/or other regulatory agencies national, state or local requirements, and the maintenance of adequate and accurate clinical records. Electronic case report forms are reviewed to ensure that key safety and efficacy data are collected and recorded as specified by the protocol, using the REDcap database platform. The monitor will be permitted to access subject medical records, laboratory data and other source documentation as needed to appropriately monitor the trial. Please reference Section 15 for additional information regarding data management and confidentiality.
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18.6 disclosure of data/publication

Individual subject medical information obtained as a result of this study is considered confidential and disclosure to third parties other than those noted below is prohibited. Such medical information may be given to the subject's personal physician or to other appropriate medical personnel responsible for the subject's welfare. Data generated as a result of this study are to be available for inspection on request by the FDA or other regulatory agencies, the Sponsor-Investigator and by the IRB/EC. Public presentation of data in any form will be thoroughly de-identified to ensure confidentiality.
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18.7 ethical considerations

The Investigator agrees to conduct this study in accordance with applicable United States FDA clinical trial regulations and guidelines, applicable United States FDA clinical trial regulations and guidelines, the ICH (E6) GCP guidelines, the European Union Directive 2001/20/EC for clinical trials conducted in the European Union, the IRB/EC and local legal requirements and with the Declaration of Helsinki (1989). The Investigator will conduct all aspects of this study in accordance with all national, state, and local laws of the applicable regulatory agencies.
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18.8 informed consent

The Sponsor-Investigator assumes the responsibility of obtaining written Informed Consent from each subject or the subject's legally authorized representative before any study-specific procedures are performed.  
Subjects meeting the criteria set forth in the protocol will be offered the opportunity to participate in the study. To avoid introduction of bias, the Investigator must exercise no selectivity with regard to offering eligible subjects the opportunity to participate in the study. Subjects or legal guardians of all candidate subjects will receive a comprehensive explanation of the proposed treatment, including the nature of the therapy, alternative therapies available, any known previously experienced adverse reactions, the investigational status of the study drug, their right to withdraw consent at any time, and other factors that are part of obtaining a proper Informed Consent. Subjects will be given the opportunity to ask questions concerning the study, and adequate time to consider their decision to or not to participate.  
Informed Consent will be documented by the use of a written Consent Form that includes all the elements required by FDA
regulations and ICH guidelines. The form is to be signed and dated by the subject or subject's legally authorized representative and by the person who administers the consent process. A copy of the signed form will be given to the person who signed it, the Page 47
original signed Consent Form will be filed with the subject's medical and/or research records, and copy maintained with the subject's study records. The date of the Informed Consent must be recorded in the source documents. If an amendment to the protocol changes the subject participation schedule in scope or activity, or increases the potential risk to the subject, the Informed Consent Form must be amended. Any amended Informed Consent must be approved by the IRB/EC
prior to use. The revised Informed Consent Form must be used to obtain re-consent from any subjects currently enrolled in the study if the subject is affected by the amendment, and must be used to document consent from any new subjects enrolled after the approval date of the amendment.
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18.9 institutional review board/ethics committee

The Sponsor-Investigator will assure that an appropriately constituted IRB/EC that complies with the requirements of 21 CFR
Section 56 or written assurance of compliance with ICH (E6) guidelines will be responsible for the initial and continuing review and approval of the clinical study. Before initiation of the study, the Sponsor-Investigator or designee will forward copies of the protocol and Consent Form to be used for the study to the IRB/EC for its review and approval. The Sponsor-Investigator or designee will also assure that all changes in the research activity and all unanticipated problems involving risks to human subjects or others will be reported promptly to the IRB/EC, and that no changes will be made to the protocol without prior IRB approval, except where necessary to eliminate apparent immediate hazards to human subjects.  
The Sponsor-Investigator or designee must notify the IRB of SAEs occurring at the site and of safety reports (e.g., IND Safety Reports) received from EMD Serono, in accordance with the IRB's policies.  
The Investigator or designee will be responsible for submitting periodic progress reports to the IRB at intervals appropriate to the degree of subject risk involved in the study, but not less than once per year and at the completion or termination of the study.
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18.10 subject privacy

The Sponsor-Investigator affirms and will uphold the principle of the subject's right to privacy. The Sponsor-Investigator shall comply with applicable national and local privacy laws.
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19.0 appendices

19.1 **APPENDIX A: ECOG Performance Status Scale**
ECOG Performance Status Scale  
| GRADE   | SCALE                                                                                                                                                     |
|---------|-----------------------------------------------------------------------------------------------------------------------------------------------------------|
| 0       | Fully active, able to carry out 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, office work |
| 2       | Ambulatory and capable of all self-care but unable to carry out work activities. Up and about more than 50% of waking  hours.                             |
| 3       | Capable of only limited self-care, confined to bed or chair more than 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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19.2 appendix b karnofsky performance

| General                                                                                         | Index                                                                        | Specific Criteria                                                           |         |        |    |               |
|-------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------|-----------------------------------------------------------------------------|---------|--------|----|---------------|
| Able to carry on normal activity; no special care  needed                                       | 100                                                                          | Normal, no complaints, no evidence of disease                               |         |        |    |               |
| 90                                                                                              | Able to carry on normal activity, minor signs or  symptoms of disease        |                                                                             |         |        |    |               |
| 80                                                                                              | Normal activity with effort, some signs or  symptoms of disease              |                                                                             |         |        |    |               |
| Unable to work, able to live at home and care for                                               | 70                                                                           | Care for self, unable to carry on normal activity                           |         |        |    |               |
| most                                                                                            | personal                                                                     | needs,                                                                      | varying | amount | of | or to do work |
| assistance needed                                                                               | 60                                                                           | Requires occasional assistance from others  but able to care for most needs |         |        |    |               |
| 50                                                                                              | Requires considerable assistance from others  and frequent medical care      |                                                                             |         |        |    |               |
| Unable to care for self, requires institutional or  hospital care or equivalent; disease may be | 40                                                                           | Disabled; requires special care and assistance                              |         |        |    |               |
| rapidly progressing                                                                             | 30                                                                           | Severely disabled, hospitalization indicated,  death not imminent           |         |        |    |               |
| 20                                                                                              | Very sick, hospitalization necessary, active  supportive treatment necessary |                                                                             |         |        |    |               |
| 10                                                                                              | Moribund                                                                     |                                                                             |         |        |    |               |
| 0                                                                                               | Dead                                                                         |                                                                             |         |        |    |               |  
19.3 **APPENDIX C: Study Calendar**
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study flow chart (for phase

Please note phase I and phase II schedules differ in that subjects on the phase I portion are required to be evaluated weekly up to week 7. Subjects on the phase II portion of the study and subjects on the phase I portion following week 7 are not required to be evaluated during weeks when they are not receiving therapy.  
The study calendar will be managed in Weeks, with each dose of each drug being noted by a Cycle. For example, assuming there are no deviations from the planned schedule events, Week 1 will have Cycle 1 of avelumab and trabectedin. Week 3 will have Cycle 2 of avelumab, Week 4 will have Cycle 2 of trabectedin, Week 5 will have Cycle 3 of avelumab, Week 7 will have Cycle 4 of avelumab and Cycle 3 of trabectedin, etc. This may change based on dose delays or modifications. Weeks should be counted sequentially regardless of what number the dose of each agent is.  
| 9717 / RG9217009                                             | 30D       |     |      |     |     |     |      |      |      |           |              |        |
|--------------------------------------------------------------|-----------|-----|------|-----|-----|-----|------|------|------|-----------|--------------|--------|
| Treatment Week                                               | Screening | 1   | 213  | 3   | 4   | 5   | 613  | 7+10 | EOT  | Post  EOT | 90 Day  Post | LTFU12 |
| EOT12                                                        |           |     |      |     |     |     |      |      |      |           |              |        |
| Scheduling Window (Days)                                     | ± 3       | ± 3 | ± 3  | ± 3 | ± 3 | ± 3 | ± 3  | ± 3  | ± 7  | ± 7       | Q12W         |        |
| Drug Administration1                                         | None      | A+T | None | A   | T   | A   | None | A+T  | None | None      | None         |        |
| Echo/MUGA2                                                   | X         | X2  |      |     |     |     |      |      |      |           |              |        |
| Informed Consent, IC/EC  Review, Demographnics and           | X         |     |      |     |     |     |      |      |      |           |              |        |
| Med History Prior and Con-Med Review                         | X         | X   | X    | X   | X   | X   | X    | X    | X    | X         | X            |        |
| Post-study anticancer  therapy status                        | X         | X   | X    |     |     |     |      |      |      |           |              |        |
| Survival Status                                              | X         | X   | X    | X   |     |     |      |      |      |           |              |        |
| Review Adverse Events                                        | X         | X   | X    | X   | X   | X   | X    | X    | X    | X         |              |        |
| Full Physical Examination (to  include vitals, weight, ECOG) | X         |     |      |     |     |     |      |      |      |           |              |        |
| Directed Physical  Examination (to include                   | X         | X   | X    | X   | X   | X   | X    | X    | X    |           |              |        |
| vitals, weight, ECOG) ECG (Phase 1 only)                     | X         | X   | X    |     |     |     |      |      |      |           |              |        |
| Pregnancy Test - Serum  (WCBP Only)3                         | X         | X   | X    | X   | X3  | X   | X    |      |      |           |              |        |
| PT/INR and aPTT                                              | X         |     |      |     |     |     |      |      |      |           |              |        |
| CBC with Differential, Blood  Chemistry5                     | X5        | X   | X    | X   | X   | X   | X    | X    | X    | X         |              |        |
| Urinalysis                                                   | X         |     |      |     |     |     |      |      |      |           |              |        |
| CK                                                           | X         | X   | X    | X6  | X   | X   |      |      |      |           |              |        |
| T3, FT4 and TSH7                                             | X         | X7  | X    | X   |     |     |      |      |      |           |              |        |
| Tumor Imaging8                                               | X         | X8  | X8   |     |     |     |      |      |      |           |              |        |
| Archival Tissue Collection  (slides)11                       | X         |     |      |     |     |     |      |      |      |           |              |        |
| Correlative Studies Blood  Collection9                       | X         | X   | X    | X9  | X   |     |      |      |      |           |              |        |
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study flow chart (for phase

1A= Avelumab, T = Trabectedin. Avelumab is administered every 2 weeks. Trabectedin is administered every 3 weeks for Cycle 1 and 2 (Week 1 and Week 4), and every 4 weeks after that (Week 7, Week 11, Week 15,…). Trabectedin may be given every 5 weeks if required due to toxicity (see section 9). Please reference Section 7 for additional details.  
2ECHO or MUGA to be completed at baseline, week 6, and every 12 weeks while on trabectedin, beginning with week 18. 3Serum pregnancy test to be performed at baseline, and every 2 weeks (or every visit where avelumab is to be administered). Serum pregnancy will also be collected at end of treatment and 30 day follow-up visit. Women of childbearing potential only. 5Amylase and Lipase are only to be collected at baseline. Chemistry and LFT panel should include sodium, chloride, potassium, glucose, blood urea nitrogen (BUN), creatinine, calcium, AST, ALT, total bilirubin, alkaline phosphatase, lactic acid dehydrogenase, total protein, and albumin. Reference Table 1 for a full analyte listing. 6CK to be performed at all visits where trabectedin is administered. If trabectedin dosing schedule is modified at discretion of investigator to q4weeks or q5weeks or more, the creatine kinase draw should also be modified to follow that schedule. 7Thyroid studies should be checked at baseline, week 1, and every 6 weeks (+/- 7 days) (Week 1, Week 7, Week 13…) 8Can be done up to 28 days prior to Week 1. While on treatment, tumor imaging should be performed every 12 weeks. Subjects will have their first post-treatment scan during week 12 and every 12 weeks thereafter at the provider's discretion. Imaging schedule will continue every 12 weeks regardless of dose delays or schedule modifications. Tumor imaging will only be performed at EOT visit if not done within 4 weeks of the study visit.  
9On treatment days, correlative blood should be drawn before study related treatment is administered. Correlative blood will be collected at week 7, and then starting at week 12 every 6 weeks on a treatment day (+/- 7 days). (Week 12, Week 18, Week 24…). 10Additional treatment days where avelumab is administered as a single agent should follow the schedule for Week 3, unless otherwise noted. Additional treatment days where trabected is administered and connected/disconnected as a single agent should follow the schedule for Week 4, unless otherwise noted. Additional treatment days where both avelumab and trabectedin are administered should follow the schedule for Week 1, unless otherwise indicated. 11Archival tissue collection does not need to be completed prior to beginning protocol therapy, but every effort should be made to ensure these samples are collected. 12The 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.  
13Subjects enrolled to Phase 1 must complete weekly visits through Week 7. Subjects on the Phase II portion of the study and subjects on the Phase I portion after week 7 are not required to be evaluated during weeks when they are not receiving any therapy.
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19.5 appendix e women and

A woman is considered fertile following menarche and until becoming postmenopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
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women in the following categories

- Premenarchal - Premenopausal female with 1 of the following:
o Documented hysterectomy o Documented bilateral salpingectomy o 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 o A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 years in the absence of other biological or physiological causes.
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19.5.1.2 male of childbearing potential

- For this trial, male subjects will be considered to be of non-reproductive potential if they have azospermia (whether due to having had a vasectomy or due to an underlying medical condition).
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19.5.2 contraception guidance for females

One of the highly effective methods of contraception listed below is required during study duration and until the end of relevant systemic exposure, defined as 3 months after last treatment. Local laws and regulations may require use of alternative and/or additional contraception methods.
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highly effective contraceptive methods that

- Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation o oral o intravaginal o transdermal
- Progestogen-only hormonal contraception associated with inhibition of ovulation o oral o injectable
- 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 related to the duration of the study and the preferred and usual lifestyle of the participant.  
o It is not necessary to use any other method of contraception when complete abstinence is elected.  
o WOCBP participants who choose complete abstinence must continue to have pregnancy tests as specified in study calendar.  
o Acceptable alternate methods of highly effective contraception must be discussed in the event that the WOCBP
participants chooses to forego complete abstinence.
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highly effective methods that are

- Intrauterine device (IUD) - Intrauterine hormone-releasing system (IUS) - Bilateral tubal occlusion - Vasectomized partner a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations regarding the use of contraceptive methods for participants participating in clinical studies.
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less than highly effective contraceptive

Failure rate of > 1% per year when used consistently and correctly.  
- Male or female condom with or without spermicide. Male and female condoms cannot be used simultaneously. - Diaphragm with spermicide - Cervical cap with spermicide - Vaginal sponge with spermicide - Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mechanism of action Unacceptable Methods of Contraception
- Periodic abstinence (calendar, symptothermal, post-ovulation methods) - Withdrawal (coitus interruptus) - Spermicide only - Lactation amenorrhea method (LAM)
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19.5.3 contraception guidance for males

Male participants with female partners of childbearing potential are eligible to participate if they agree to the following during the treatment and until the end of relevant systemic exposure.  
- Inform any and all partner(s) of their participation in a clinical drug study and the need to comply with contraception instructions as directed by the investigator.  
- Male participants are required to use a condom for study duration and until the end of relevant systemic exposure defined as 5 months after last systemic dose.  
- Female partners of males participating in the study to consider use of effective methods of contraception until the end of relevant systemic exposure, defined as 5 months after last systemic dose.  
- Male participants 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 during the treatment and until 5 months after last systemic dose.
- Refrain from donating sperm for the duration of the study treatment and for5 months after last systemic dose.  
- Male participants may experience testicular side effects, such as reduced sperm production rates, reduced sperm concentrations, decreased epidydimal weights, atrophy and degeneration of the testes with aspermia (no sperm production), hypospermia (low or reduced sperm production), and cellular changes in the epididymis (a tube within the testes that transports sperm).
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19.6 appendix f references

1. Allavena P, Signorelli M, Chieppa M, et al. Anti-inflammatory properties of the novel antitumor agent yondelis
(trabectedin): inhibition of macrophage differentiation and cytokine production. *Cancer Res.* 2005;65(7):2964-2971.  
2. Germano G, Frapolli R, Simone M, et al. Antitumor and anti-inflammatory effects of trabectedin on human myxoid liposarcoma cells. *Cancer Res.* 2010;70(6):2235-2244.  
3. Germano G, Frapolli R, Belgiovine C, et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell. 2013;23(2):249-262.  
4. Bathan AJ, Constantinidou A, Pollack SM, Jones RL. Diagnosis, prognosis, and management of leiomyosarcoma:
recognition of anatomic variants. *Curr Opin Oncol.* 2013;25(4):384-389.  
5. Santoro A, Tursz T, Mouridsen H, et al. Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. *J Clin Oncol.* 1995;13(7):1537-1545.  
6. Gelderblom H, Blay JY, Seddon BM, et al. Brostallicin versus doxorubicin as first-line chemotherapy in patients with advanced or metastatic soft tissue sarcoma: An European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group randomised phase II and pharmacogenetic study. *Eur J Cancer.* 2014;50(2):388-396.  
7. Judson IR, Verjeij J, Gelderblom H, Hartman J, Schoffski P, Blay J, Paolo dei Tos A, Marreud S, Litiere S, van der Grraaf W.  
Result of a Randomised phase III trial (EORTC 62012) of single agent doxorubicin versus plus ifosfamide as first line chemotherapy for patients with advanced, soft tissue sarcoma: a suvival study by the EORTC Soft Tissue and Bone Sarcoma Group. *Oral Presentation 2013 Connective Tissue Oncology Society Meeing.* 2013.  
8. Rajendra R, Jones RL, Pollack SM. Targeted treatment for advanced soft tissue sarcoma: profile of pazopanib.  
OncoTargets and therapy. 2013;6:217-222.  
9. van der Graaf WT, Blay JY, Chawla SP, et al. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial. *Lancet.* 2012;379(9829):1879-1886.  
10. Conley AP, Trent J, Zhang W. Recent progress in the genomics of soft tissue sarcomas. *Curr Opin Oncol.* 2008;20(4):395399.  
11. Tran E, Turcotte S, Gros A, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. *Science.* 2014;344(6184):641-645.  
12. Gubin MM, Zhang X, Schuster H, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. *Nature.* 2014;515(7528):577-581.  
13. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. *Immunity.* 2014;41(1):49-61.  
14. Ganjoo KN, Witten D, Patel M, et al. The prognostic value of tumor-associated macrophages in leiomyosarcoma: a single institution study. *Am J Clin Oncol.* 2011;34(1):82-86.  
15. Espinosa I, Beck AH, Lee CH, et al. Coordinate expression of colony-stimulating factor-1 and colony-stimulating factor-1related proteins is associated with poor prognosis in gynecological and nongynecological leiomyosarcoma. *Am J Pathol.*
2009;174(6):2347-2356.  
16. Edris B, Weiskopf K, Volkmer AK, et al. Antibody therapy targeting the CD47 protein is effective in a model of aggressive metastatic leiomyosarcoma. *Proc Natl Acad Sci U S A.* 2012;109(17):6656-6661.  
17. Demetri GD, von Mehren M, Jones RL, et al. Efficacy and Safety of Trabectedin or Dacarbazine for Metastatic Liposarcoma or Leiomyosarcoma After Failure of Conventional Chemotherapy: Results of a Phase III Randomized Multicenter Clinical Trial. *J Clin Oncol.* 2016;34(8):786-793.  
18. Larsen AK, Galmarini CM, D'Incalci M. Unique features of trabectedin mechanism of action. Cancer chemotherapy and pharmacology. 2015.  
19. Ueda T, Kakunaga S, Ando M, et al. Phase I and pharmacokinetic study of trabectedin, a DNA minor groove binder, administered as a 24-h continuous infusion in Japanese patients with soft tissue sarcoma. *Invest New Drugs.*
2014;32(4):691-699.  
20. Cuevas C, Francesch A. Development of Yondelis[registered sign] (trabectedin, ET-743). A semisynthetic process solves the supply problem. *Natural Product Reports.* 2009;26(3):322-337.  
21. Martínez-Serra J, Maffiotte E, Martín J, et al. Yondelis® (ET-743, Trabectedin) sensitizes cancer cell lines to CD95mediated cell death: New molecular insight into the mechanism of action. *European Journal of Pharmacology.*
2011;658(2–3):57-64.  
22. Allavena P, Signorelli M, Chieppa M, et al. Anti-inflammatory Properties of the Novel Antitumor Agent Yondelis
(Trabectedin): Inhibition of Macrophage Differentiation and Cytokine Production. *Cancer Research.* 2005;65(7):29642971.  
23. Germano G, Frapolli R, Belgiovine C, et al. Role of Macrophage Targeting in the Antitumor Activity of Trabectedin. *Cancer* Cell. 2013;23(2):249-262. 24. Galmarini C, \#039, Incalci M, Allavena P. Trabectedin and Plitidepsin: Drugs from the Sea that Strike the Tumor Microenvironment. *Marine Drugs.* 2014;12(2):719-733.  
25. D'Incalci M, Badri N, Galmarini CM, Allavena P. Trabectedin, a drug acting on both cancer cells and the tumour microenvironment. *Br J Cancer.* 2014;111(4):646-650.  
26. Bonfanti M, La Valle E, Fernandez Sousa Faro JM, et al. Effect of ecteinascidin-743 on the interaction between DNA
binding proteins and DNA. *Anti-Cancer Drug Design.* 1999;14(3):179-186.  
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