Table 2.

Schedule of events

VISITS	VISIT 1a	VISIT 2b	VISIT 3b	VISIT 4b	VISIT 5b	VISIT 6b	END OF STUDY VISITC	Unsched-uled Visitd	SirAE Visite	Optional ‘special case’ SirAE biopsiesf
TREATMENT CYCLE (Combination ipilimumab/nivolumab, single agent pembrolizumab, nivulumab or atezolizumab, or switch between these therapies or to another CPI treatment / regimen	CYCLE 1 -14 days (Baseline)	CYCLE 2 +/-7 days	CYCLE 3 +/-7 days	CYCLE 4 +/-7 days	CYCLE dependent upon drug regimen b +/-7 days	CYCLE dependentupon drug regimenb +/-7 days
Procedures
Discuss Study	X
Sign consent form	Xg								Xh	Xh
Pregnancy test	X	Xi	Xi	Xi	Xi	Xi	Xi	Xi	Xi	Xi
Concomitant meds recording	X	X	X	X	X	X	X	X		X
General physical examination	X	Xj	Xj	Xj	Xj	Xj	Xj	Xj		Xj
Adverse event assessment	X	X	X	X	X	X	X	X		X
Questionnairek	X	X	X	X	X	X	X	X		X
Blood test (NHS Lab)l	X	X	X	X	X	X	X	X		X
Research blood testm	X	X	X	X	X	X	X		X	X
Skin swabsn	X	X	X	X	X		X		X
Stool Sample (optional)o	X	X	X	X	X		X		X
Photography of skin IrAEs (optional)p		X	X	X	X	X	X	X
Skin Biopsy for research (optional)q									X	X
Endoscopic biopsies for research (consenting patients with GI SirAEs only)r.									X	X

a Baseline procedures should be performed within 14 days of receiving of administration of the first dose of combination ipilimumab/nivolumab, or single agent pembrolizumab, nivolumab or atezolimumab

b Study visits to occur within +/-7 days of receiving CPI for visits 2, 3, 4, 5 and 6. Cycles of CPI treatment are scheduled to occur at:

i Nivolumab (3-weekly)/ipilimumab (3- or -6 weekly) x 4 cycles, followed 6 weeks after combination treatment by 4-weekly single agent Nivolumab) (melanoma) weeks 3, 6, 9, 15 and 39 (i.e. cycles 2, 3, 4, 5 and 11)

ii Nivolumab (melanoma) weeks 4, 8, 12, 16 and 40 (i.e. cycles 2, 3, 4, 5 and 11)

iii Pembrolizumab (3-weekly, followed by 6-weekly after week 9 or 12) (melanoma), weeks 3, 6 and 9, then week 15 or 18 and week or 39 or 36 (i.e. cycles 2, 3, 4, 5 or 6 and 9)

iv. Pembrolizumab (6-weekly) (melanoma) weeks 6, 12, 18, 24 and 36 (i.e. cycles 2, 3, 4, 5 and 7)

v Pembrolizumab 4 × 3-weekly followed by 6-weekly after week 12 (NSCLC), weeks 3, 6, 9, 18 and 36 (i.e. cycles 2, 3, 4, 6 and 9)

vi Atezolizumab 4-weekly (NSCLC) weeks 4, 8, 12, 16 and 40) (i.e. cycles 2, 3, 4, 5 and 11)

vii Nivolumab(3-weekly)/ipilimumab(6-weekly) (Mesothelioma) weeks 3, 6, 9, 15 and 36 (i.e. cycles 2, 3, 4, 6 and 13)

c End of Study Visit, if applicable, i.e. if a patient’s treatment ends before completing the follow up visits and for a reason other than a SirAE Visit to be completed within 14 days of the decision to end treatment

d An unscheduled visit is only required at the discretion of the investigator if the participant contacts the research team with a new possible irAE (see Sect. 7.6)

e Wherever possible the SirAE visit (and all of the listed procedures except optional gut biopsy) should be combined with the scheduled or unscheduled visit at which the SirAE is determined to have occurred, unless a scheduled or unscheduled visit has already been performed within post 7 days (or 14 days if a standard of care gut or skin biopsy with a research biopsy is being performed) of identification of the SirAE (see Sect. 7.7), in which instance the SirAE procedures should be carried out alone. Some of the SirAE procedures may require a separate visit when the SirAE event can only be confirmed when blood results are available or for gastrointestinal or skin SirAEs where the patient consents to gut or skin biopsy

f Optional ‘special case’ SirAE biopsies when standard of care gut or skin biopsy occur later than 14 days post initial identification of an SirAE whilst on CPI treatment. Optional research biopsies will be allowed at any time point that standard of care biopsies occur, until what would have been the patient’s final scheduled study visit if no SirAEs had occurred. Research procedures listed in the above table will be performed on the same day as the research biopsy (if not already performed within 7 days of the biopsy)

g Main study and (optional) for stool sample donation and also (optional) for a skin biopsy where indicated

h For obtaining gut biopsies for research from patients experiencing gastrointestinal SirAEs undergoing lower gastrointestinal tract endoscopies as part of routine care under direction of consulting gastroenterologist (optional), or for a skin biopsy where indicated (optional)

i Female patients will be asked whether they might be pregnant at each study visit and a pregnancy test conducted if relevant

j Physical exam as applicable, as per standard of care

k Symptom-directed questionnaire; Appendix 1

l FBC, U&E, LFT, TFT, Magnesium (standard of care tests) ESR, CRP (non-standard of care tests). At an End of Study visit FBC to be done as a research blood, if not being done as standard of care

m 4 × 10mL EDTA, 1 × 8.5mL serum, 1 × 10mL heparin

n. Skin swabs from forehead, upper chest, upper back, dorsum of the hand and forearm at each visit with potential additional swab from a site of vitiligo-like depigmenting rash if occurs. Skin swabs applicable only for up to the first 53 evaluable participants

o Only for patients who consented at baseline to stool sample collection. Stool collection applicable only for up to the first 53 evaluable participants

p Only for patients who consented at baseline to photography of skin IrAEs

q Only for patients who consent to optional skin biopsy of affected skin

r Only for patients who consent at time incident IrAE determined