media.nature.com · web viewif cbc or platelets lead to a -1 dose level reduction per table above,...

Supplementary Table S1. Recommended dose modification for each treatment arm based on

the worst grade (as per NCI CTCAE criteria, version 4.03) observed during a treatment cycle

and in the prior treatment cycle.

Infusion times for the standard of care chemotherapy drugs below is per package insert. Pre-

medications per institutional guidelines.

Arm 1: Gemcitabine

Dose level Gemcitabine dose

1 1000 mg/m2 on day 1 and day 8 every 21 days

-1 800 mg/m2 on day 1 and day 8 every 21 days

-2 600 mg/m2 on day 1 and day 8 every 21 days

Arm 2: Gemcitabine and docetaxel

Dose level Gemcitabine dose Docetaxel dose

1 900 mg/m2 on day 1 and day 8 every 21

days

75 mg/m2 on day 8 every 21 days

-1 800 mg/m2 on day 1 and day 8 every 21

days


-2 600 mg/m2 on day 1 and day 8 every 21

days


1

Arm 3a (treatment naïve): Gemcitabine and nab-paclitaxel

Dose level Gemcitabine dose Nab-paclitaxel dose

1 1000 mg/m2 on day 1 and day 8 every

21 days

125 mg/m2 on day 1 and day 8 every 21

days

-1 800 mg/m2 on day 1 and day 8 every

21 days


days


21 days


days

Arm 3b (previously treated): Gemcitabine and nab-paclitaxel

Dose level Gemcitabine dose Nab-paclitaxel dose


21 days


days


21 days


days

-2 600 mg/m2 on day 1 every 21 days 60 mg/m2 on day 1 every 21 days

Arm 4: Gemcitabine and vinorelbine

Dose level Gemcitabine dose Vinorelbine dose


21 days


days


21 days


days


21 days


days

2


21 days


days

Arm 5: Irinotecan

Dose level Irinotecan dose

1 300 mg/m2 on day 1 every 21 days

-1 250 mg/m2 on day 1 every 21 days



Arm 6: Liposomal doxorubicin

Dose level Liposomal doxorubicin dose

1 30 mg/m2 on day 1 every 21 days




3

Dose Delay and Intervention Guidelines for Pembrolizumab (P)

Grade Action

Grade 1 immune related

adverse reaction

No action. Provide symptomatic treatment.

Grade 2 immune related

adverse reaction*

May withhold P.

Consider systemic corticosteroids in addition to appropriate

symptomatic treatment.

Grade 3 and Grade 4 immune

related immune adverse

reaction*

Withhold P.

Discontinue if unable to reduce corticosteroid dose to < 10 mg

per day prednisolone equivalent within 12 weeks of toxicity.

Systemic corticosteroids are indicated in addition to

appropriate symptomatic treatment. May utilize 1 to 2 mg/kg

prednisolone or equivalent per day.

Steroid taper should be considered once symptoms improve to

Grade 1 or less and tapered over at least 4 weeks

*Chemotherapy may be continued as long as there are no contraindications.

Severe or life-threatening adverse reactions, including any of the following:

Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency

(7 or more over baseline), stool incontinence, need for intravenous hydration for more

than 24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation.

4

Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper

limit of normal or total bilirubin >3 times the upper limit of normal.

Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full

thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations

Severe motor or sensory neuropathy, Guillain-Barre syndrome, or myasthenia gravis

Severe immune-mediated reactions involving any organ system (e.g., nephritis,

pneumonitis, pancreatitis, non-infectious myocarditis)

Immune-mediated ocular disease that is unresponsive to topical immunosuppressive

therapy

Dose Delay and Reduction Guidelines for Arm 1: Gemcitabine plus P

Absolute Granulocyte Count

(x 109/L)

Platelet Count

(x 109/L)

% of Full Dose

≥ 1000 AND ≥ 100,000 100

500-999 OR 50,0000-99,9999 -1 dose level

< 500 OR < 50,0000 HOLD

For Day 1 of each cycle:

Any clinically significant treatment-related toxicity must return to baseline or at least grade 1,

AND subject is receiving less than 7.5 mg prednisone or equivalent per day.


If CBC or platelets lead to a -1 dose level reduction per table above, this applies only to Day 8

dosing, and if the CBC with differential and serum chemistries are confirmed to be within dosing

parameters (inclusion #7 and 8) on the subsequent cycle’s Day 1, the patient will return to the

previous dose level (e.g. if patient is on dose level 1 of gemcitabine [1000 mg/m2], and on Day

5

8, has an ANC between 500-999 or platelets between 50,000-99,999, then Day 8 dosing will be

800 mg/m2. At the next cycle Day 1 and Day 8, if the ANC is ≥ 1000 and platelets ≥ 100,000, the

gemcitabine dose will be 1000 mg/m2.

When chemotherapy requires holding because of hematologic toxicity, reduce by 1 dose level in

subsequent cycles.

* Discontinue the chemotherapy agent after 2 dose reductions.

Dose Modifications for Non-Hematologic Adverse Reactions

Permanently discontinue gemcitabine for any of the following:

Unexplained dyspnea or other evidence of severe pulmonary toxicity

Severe hepatic toxicity

Hemolytic-Uremic Syndrome

Capillary Leak Syndrome

Posterior reversible encephalopathy syndrome

Withhold gemcitabine or reduce dose by one dose level for other severe (Grade 3 or 4) non-

hematological toxicity until resolved. No dose modifications are recommended for alopecia,

nausea, or vomiting.

6

Dose Delay and Reduction Guidelines for Arm 2: Gemcitabine and Docetaxel plus P

For gemcitabine:


(x 109/L)

Platelet Count

(x 109/L)

% of Full Dose

≥ 1000 AND ≥ 100,000 100

500-999 OR 50,0000-99,9999 -1 dose level

< 500 OR < 50,0000 HOLD

For docetaxel:


(x 109/L)

Platelet Count

(x 109/L)

% of Full Dose

At least 1,500 AND ≥ 100,000 100

< 1500 OR 50,0000-99,9999 HOLD








previous dose level.

7


subsequent cycles. Discontinue the chemotherapy agent after 2 dose reductions.

Dose Modifications for Non-Hematologic Adverse Reactions

Permanently discontinue gemcitabine and docetaxel for any of the following:






Withhold gemcitabine and/or docetaxel or reduce each dose by 1 dose level for other severe

(Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are

recommended for alopecia, nausea, or vomiting.

Dose Delay and Reduction Guidelines for Arm 3: Gemcitabine and Nab-paclitaxel plus P

Day 1 of cycle Hematologic Toxicity:


(x 106/L)

Platelet Count

(x 106/L)

Timing

≥ 1.5 x 109/L AND ≥ 100 x 109/L Treat

< 1.5 x 109/L OR ≥ 100 x 109/L Delay by 1 week intervals

until recovery

Day 1 of cycle Non-Hematologic Toxicity:

Toxicity/dose held Gemcitabine/Gemcitabine + Nab-paclitaxel

8

Grade 0-2 Same as Day 1 of previous cycle (except for

grade 2 cutaneous toxicity where doses of

gemcitabine and nab-paclitaxel should both be

reduces to next lower level).

Grade 3 toxicity Decrease gemcitabine and nab-paclitaxel to

next lower dose level.

* If toxicity only affects neuropathy only reduce

nab-paclitaxel.

Grade 4 toxicity Off treatment

* Pulmonary Embolism (per CTCAE) if mild or

asymptomatic is exempt from this.

* If toxicity only affects neuropathy only reduce

nab-paclitaxel.

Dose held in 2 previous consecutive cycles Decrease gemcitabine to next lower dose level

and continue throughout the rest of the

treatment.

Dose Modification for Hematologic Toxicity within a cycle:

Day 8 Counts Day 8 nab-

paclitaxel

Day 8

gemcitabine

All treatment days

nab-paclitaxel

All treatment days

gemcitabine

ANC > 1000

and Platelets ≥

75,000

100% 100%

ANC 500-1000 Decrease Decrease

9

or Platelets

50,000- 74,999

dose by 1

level

dose by 1

level

ANC < 500 or

Platelets <

50,000

HOLD HOLD

Febrile

Neutropenia

(Grade 3 or 4)

HOLD

Upon resuming

dosing, decrease to

next lower dose

level and do not re-

escalate throughout

the rest of the

treatment.

HOLD

Upon resuming

dosing, decrease to

next lower dose level

and do not re-

escalate throughout

the rest of the

treatment.

Recurrent

Febrile

Neutropenia

(Grade 3 or 4)

Decrease to next

lower dose level and

do not re escalate

throughout the rest

of the treatment.

Decrease to next

lower dose level and

do not re escalate

throughout the rest of

the treatment.

Dose Modification for Non-Hematologic Toxicity within a cycle:

CTCAE Grade Percent of Day 1 Nab-paclitaxel +

gemcitabine Dose

0-2

* and Grade 3 nausea/vomiting and alopecia

100% (except for cutaneous toxicity)

10

3

* except nausea/vomiting and alopecia

Hold either one or both drugs (except

cutaneous toxicity) until resolution to ≤ Grade

1. Then resume treatment at the next lower

dose level.

4

HOLD

(Depend on PI judgment)

(Pulmonary embolism, Grade 4 in the CTCAE

tables, if mild or asymptomatic, will be exempt

from this requirement)

Peripheral Neuropathy:

Nab-paclitaxel treatment should be withheld in patients who experience ≥ Grade 3 peripheral

neuropathy. Gemcitabine administration can continue during this period. Nab-paclitaxel

treatment may be resumed at the next lower dose level in subsequent cycles after the

peripheral neuropathy improves to ≤ Grade 1. Patients experiencing peripheral neuropathy that

requires a delay in scheduled nab-paclitaxel dosing for ≥ 21 days will discontinue study

treatment. The time to resolution to Grade ≤ 1 should be the adverse event duration used for

adverse event reporting.

Cutaneous Toxicity:

Patients who develop Grade 2 or 3 cutaneous toxicity should have their dose reduced to the

next lower dose level for both drugs. If the patient continues to experience these reactions,

despite dose reduction, treatment should be discontinued. Patients who develop Grade 4

cutaneous toxicity should have treatment discontinued.

Gastrointestinal Toxicity:

11

If Grade 3 mucositis or diarrhea occurs, study drug should be withheld until resolution to ≤

Grade 1, then reinstituted at the next lower dose level of both drugs. Patients who develop

Grade 4 mucositis or diarrhea should have treatment discontinued.

Pulmonary Embolism:

Asymptomatic or clinically mild pulmonary embolism can be treated with low-molecular-weight

heparin without interruption of therapy. Moderate to severe pulmonary embolism will require

permanent discontinuation of treatment.

All other grade 3 or 4 non-hematologic toxicities: withhold gemcitabine and/or nab-paclitaxel or

reduce each dose by 1 dose level for other severe (Grade 3 or 4) until resolved. No dose

modifications are recommended for alopecia, nausea, or vomiting.

12

Dose Delay and Reduction Guidelines for Arm 4: Gemcitabine and Vinorelbine P

For gemcitabine:


(x 109/L)

Platelet Count

(x 109/L)

% of Full Dose

≥ 1000 AND ≥ 100,000 100

500-999 OR 50,0000-99,9999 -1 dose level

< 500 OR < 50,0000 HOLD

For vinorelbine:


(x 109/L)

Platelet Count

(x 109/L)

% of Full Dose

At least 1,500 AND ≥ 100,000 100

< 1500 OR 50,0000-99,9999 HOLD








previous dose level.

13



Dose Modifications for Non-Hematologic Adverse Reactions:

Permanently discontinue gemcitabine and vinorelbine for any of the following:






Grade ≥2 neurotoxicity develops

Withhold gemcitabine and/or vinorelbine or reduce each dose by 1 dose level for other severe

(Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are

recommended for alopecia, nausea, or vomiting.

Dose Delay and Reduction Guidelines for Arm 5: Irinotecan plus P

For irinotecan:


(x 109/L)

Platelet Count

(x 109/L)

% of Full Dose

At least 1,500 AND ≥ 100,000 100

< 1500 OR 50,0000-99,9999 HOLD



14

Dose Modifications For Non-Hematologic Adverse Reactions:

Withhold irinotecan or reduce by 1 dose level for other severe (Grade 3 or 4) non-hematological

toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or

vomiting.

Dose Delay and Reduction Guidelines for Arm 6: Liposomal doxorubicin plus P

For liposomal doxorubicin:


(x 109/L)

Platelet Count

(x 109/L)

% of Full Dose

At least 1,500 AND ≥ 100,000 100

< 1500 OR 50,0000-99,9999 HOLD



Dose Modifications for Non-Hematologic Adverse Reactions:

Where a % dose reduction is listed, instead reduce the dose by 1 dose level.

Hand-Foot Syndrome (HFS)

Toxicity Grade Dose Adjustment

1

Mild erythema, swelling, or desquamation not

interfering with daily activities.

Re-dose unless patient has experienced

previous Grade 3 or 4 HFS.

If so, delay up to 2 weeks and decrease dose

by 25%. Return to original dose interval.

2 Delay dosing up to 2 weeks or until

15

Erythema, desquamation, or swelling

interfering with, but not precluding normal

physical activities; small blisters or

ulcerations less than 2 cm in diameter.

resolved to Grade 0-1.

If after 2 weeks there is no resolution,

doxorubicin should be discontinued. If resolved

to Grade 0-1 within 2 weeks, and there are no

prior Grade 3-4 HFS continue treatment at

previous dose and return to original dose

interval. If patient experienced previous Grade

3-4 toxicity, continue treatment with a 25%

dose reduction and return to original dose

interval.

3

Blistering, ulceration, or swelling interfering

with walking or normal daily activities; cannot

wear regular clothing.

Delay dosing up to 2 weeks or until


Decrease dose by 25% and return to original

dose interval. If after 2 weeks there is no

resolution, doxorubicin should be discontinued.

4

Diffuse or local process causing infectious

complications, or a bedridden state or

hospitalization.






Stomatitis

Toxicity Grade Dose Adjustment

1 Re-dose unless patient has experienced

16

Painless ulcers, erythema, or mild soreness previous Grade 3 or 4 toxicity.

If so, delay up to 2 weeks and decrease dose

by 25%. Return to original dose interval.

2

Painful erythema, edema, or ulcers, but can

eat



If after 2 weeks there is no resolution,

doxorubicin should be discontinued. If resolved

to Grade 0-1 within 2 weeks, and there are no

prior Grade 3-4 stomatitis, continue treatment

at previous dose and return to original dose

interval. If patient experienced previous Grade

3-4 toxicity, continue treatment with a 25%

dose reduction and return to original dose

interval.

3

Painful erythema, edema, or ulcers, and

cannot eat






4

Requires parenteral or enteral support



Decrease dose by 25% and return to

doxorubicin original dose interval. If after 2

weeks there is no resolution, doxorubicin

should be discontinued.

17

Withhold liposomal doxorubicin or reduce by 1 dose level for other severe (Grade 3 or 4) non-

hematological toxicity until resolved. No dose modifications are recommended for alopecia,

nausea, or vomiting.

18

Supplementary Table S2. Patient level adverse events

Subject #AEs (Event and Highest

Grade)

Number of dose

reductions/ delay or skipped

(reduced / delayed or

skipped on

cycle/day)

Reason for dose reduction or delay

Last infusion given

1-0001

Anemia NOS gr2; vomiting gr1;

pain in extremity gr2;

hyperphosphatemia gr1

N/A N/A

C3 D8

1-0002

Fever gr1; WBC decreased

gr2; AST elevated gr1;

anorexia gr2; fatigue gr3;

xerostomia gr1; cough gr2

N/A N/A

C3 D8

1-0003

Neutropenia gr4; WBC

decreased gr3;

thrombocytopenia gr1;

mucositis oral gr1; headache

gr1; ALT elevated gr1; AST

elevated gr2

C1 D8

C3 D1

Gr4 neutropenia

Gr3 neutropenia

C3 D8

1-0004


decreased gr3;

thrombocytopenia gr1; rash

NOS gr2; anemia NOS gr 2;

AST elevated gr3; ALT elevated gr3; vomiting gr2;

small bowel obstruction gr3

Planned

C3 D1

Gr3 AST and ALT elevation

C2 D1

1-0005Edema gr1; AST elevated gr3,

ALT elevated gr3

N/A N/AC1 D8

19

1-0006

WBC decreased gr3;

neutropenia gr3; fatigue gr1;

vomiting gr1; rash NOS gr1;

hypophosphatemia gr1;

vaginal hemorrhage gr1; AST

elevated gr1; ALT elevated gr1

C2 D8 Gr3 neutropenia

C3 D8

2-0001

Rash NOS gr1; weight loss

gr1; thrombocytopenia gr1;

dysgeusia gr1; fatigue gr1;

edema in limbs gr1; tracheal

hemorrhage gr1; WBC

decreased gr3; neutropenia

gr3; syncope gr3; hematoma

gr1; pain in extremity gr1;

anemia NOS gr2;

hyponatremia gr1;

hypertension gr 1; pleural

effusion gr2

C2 D8

C3 D8

Gr3 neutropenia

Gr3 neutropenia

C5 D8

3-0001 Hypomagnesemia gr1;

diarrhea gr1; fatigue gr2; PPE

gr1; sinusitis gr2; AST elevated gr1; ALT elevated gr1; dysgeusia gr1; abdominal

pain gr1; insomnia, gr 1;

mucositis oral gr1; arthralgias gr1; hypoalbuminemia gr2;

pain in extremity gr1;

epistaxis gr1; edema in limbs

gr1; anemia NOS gr2;

pneumonia gr3, COPD

exacerbation gr2; pruritus gr1;

hyponatremia gr3; dyspnea

gr3; rash NOS gr1; fever gr1; capillary leak syndrome gr3;

C4 D8

C7 D8

C10 D8

C11 D1

Gr3 device infection

Gr2 upper respiratory

infection + Gr2 COPD

exacerbation

Gr3 capillary leak syndromeGr3 hyponatremia + Gr2

fatigue

C11 D8

20

chills gr1; upper respiratory

infection gr2; creatinine

increased gr1; thrombotic

event gr2; device infection gr3

3-0002

Fever gr2; thrombocytopenia

gr3; neutropenia gr3; anemia

NOS gr2; fatigue gr2; ALT

increased gr1; mucositis oral

gr1; WBC decreased gr2;

epistaxis gr1; presyncope gr2

C1 D8

C2 D8

C3 D8

Gr3 thrombocytopenia +

Gr1 neutropenia + Gr2

anemia

Gr2 thrombocytopenia +

Gr2 neutropenia

Gr3 neutropenia

C7 D8

3-0003

Constipation gr1; rash NOS gr1; vomiting gr1; anemia

NOS gr2; weight loss gr1;

hypokalemia gr2;

hyponatremia gr1; AST elevated gr1; hyperkalemia

gr1; hypoalbuminemia gr1;

fever gr1; insomnia gr1; ALK

elevated gr1

N/A N/A

C7 D8

3-0004

Insomnia gr1; rash NOS gr2;

dysgeusia gr1; dehydration

gr2; weight loss gr1; chills gr1; fever gr1; hypokalemia

gr1; pneumonitis gr2;

mucositis oral gr1;

thrombocytopenia gr3; ALT elevated gr1; thrombotic event

gr2; cholangitis gr3; anemia

NOS gr2; neutropenia gr3

C3 D1

C17 D1

Gr2 pneumonitisGr3 thrombocytopenia

C17 D8

3-0005 Fatigue gr2; vomiting gr2;

nausea gr2; dehydration gr2;

anemia NOS gr2;


hyponatremia gr3; ALT

C1 D8 Gr3 hyponatremia + Gr2

fatigue + Gr3

thrombocytopenia

C1 D1

21

elevated gr1; edema in limbs


thrombotic event gr3

3-0006N/A N/A N/A Screen

Fail

3a-0007

Anemia NOS gr2; rash NOS gr2; cough gr1; neutropenia

gr1; pain in extremities gr1;

peripheral sensory neuropathy

gr1; hot flashes gr1

N/A N/A

C15 D8

3a-0008

Pruritus gr1; AST elevated gr2; ALT elevated gr2; diarrhea gr2; peripheral

sensory neuropathy gr3;

anemia NOS gr2; fatigue gr1; hot flashes gr1; fever gr1

Planned

C6 D1

Gr3 peripheral sensory

neuropathy

C5 D8

3a-0009

Dehydration gr2; vomiting gr1;

nausea gr1; fatigue gr2;

anorexia gr1; AST elevated

gr3; ALT elevated gr3,

peripheral sensory neuropathy

gr1

N/A N/A

C7 D8

3a-0010

Thrombocytopenia gr2;

insomnia gr1; diarrhea gr1;

anemia NOS gr2, pain in

extremities gr1; peripheral

sensory neuropathy gr1

N/A N/A

C7 D8

3b-0011

Vaginal hemorrhage gr1; pain

in extremity gr1; abdominal

pain gr1; rectal hemorrhage

gr1; constipation gr1; ALK

elevated gr3

Planned

C2 D1

Gr3 ALK elevated

C2 D1

22

3-0012Intentionally blank-this patient

enrolled on phase II of arm 3a

N/A N/A

3b-0013

Thrombocytopenia gr2; anemia

NOS gr2; vomiting gr1; ALK

elevated gr1; cough gr1; rash

NOS gr1; nausea gr1

N/A N/A

C3 D8

4-0001

Nausea gr2; hypoxia gr3;

vomiting gr2; pneumonia gr3;

thrombocytopenia gr2; anemia

NOS gr3; hypermagnesemia

gr1; diarrhea gr1;

hypercalcemia gr1; dyspnea

gr2; constipation gr1; edema

in limbs gr1; hypernatremia

gr1; hematoma gr1;

hypoalbuminemia gr1; skin

infection gr2; pulmonary

edema gr3

C1 D8

C2 D8

Gr3 hypoxia + Gr2

nausea + Gr2 vomiting

Gr3 anemia

C3 D8

4-0002

Nausea gr2; hypoxia gr3;

pneumonia gr2;

hypoalbuminemia gr1; edema

in limbs gr1; hematoma

gr1;constipation gr1; anemia

NOS gr1; thrombocytopenia

gr2; WBC decreased gr2;

arthralgia gr1; ALK elevated

gr1; AST elevated gr1; ALT

elevated gr1;

hyperphosphatemia gr1;

vomiting gr2; hypernatremia

gr1

N/A N/A

C3 D8

4-0003 Headache gr1; hypokalemia

gr1; anemia NOS gr2; WBC

N/A N/A C2 D1

23

decreased gr1; rhinorrhea gr1;

pruritus gr1

4-0004

ALK elevated gr1; AST

elevated gr1; ALT elevated

gr1; hyperphosphatemia gr1;

hypomagnesemia gr1; anemia

NOS gr2; WBC decreased gr1;


hypoalbuminemia gr1

N/A N/A

C3 D8

4-0005

Cough gr1; neutropenia gr2;

WBC decreased gr2; AST

elevated gr1; ALT elevated

gr1; ALK elevated gr1; weight

loss gr1

N/A N/A

C3 D8

4-0006


decreased gr3;

thrombocytopenia gr2; pruritis

gr1; dizziness gr1; headache

gr1

C1D8

C3D8

C4D8

Gr4 neutropenia

Gr3 neutropenia

Gr3 neutropenia C9 D1

4-0007

Hyperphosphatemia gr1;

anemia NOS gr1; WBC

decreased gr3; neutropenia

gr3; thrombocytopenia gr 1;

rash NOS gr1; insomnia gr1;

AST elevated gr2; ALT elevated gr2; headache gr2;

fever gr1; hypothyroidism gr2; constipation gr1; mucosal

infection gr2

N/A N/A

C3 D8

4-0008 Dysesthesia gr1; dizziness gr1;

diarrhea gr1; rash NOS gr1;

fatigue gr2; hypokalemia gr1;

neutropenia gr2; AST elevated

gr1; ALT elevated gr1; WBC

C2 D8

C6 D8

Gr2 neutropenia

Gr2 neutropenia

C6 D8

24

decreased gr2; pain in

extremity gr1; upper

respiratory infection gr1;

diarrhea gr1; myalgias gr2;

hearing impaired gr1; anemia

NOS gr2

4-0009

Nausea gr1; pruritus gr1;

fatigue gr1; alopecia gr1; ALT elevated gr3; AST elevated gr3; anorexia gr1; neutropenia

gr3

C2 D8

C3 D8

Gr3 elevated AST and ALTGr3 neutropenia C5 D8

4-0010

Pain in extremity gr1;

neutropenia gr3; fatigue gr2;

nausea gr1

C1 D8

C2 D8

Gr2 neutropenia

Gr3 neutropenia C3 D8

4-0011


decreased gr2; anemia NOS

gr2; fever gr2; upper

respiratory infection gr1; pain

in extremity gr1; mucositis oral

gr1; fever gr1; AST elevated gr3; ALT elevated gr2,

thrombocytopenia gr1

C1 D8

C2 D1

C4 D8

Planned

C6 D8

Gr1 thrombocytopenia

Gr2 neutropenia

Gr3 AST elevation + Gr2 ALT elevationGr3 AST elevation + Gr2 ALT elevation

C6 D1

4-0012

Pain in extremity gr1, nausea

gr1; vomiting gr1; constipation

gr1; chills gr1; pharyngitis gr1;

cough gr1; fatigue gr2; anemia

NOS gr3; thrombocytopenia gr

1; WBC decreased gr3;

neutropenia gr2;

hypoalbuminemia gr2;

hyperglycemia gr2; headache

gr1

C7 D1

C8 D1

Gr2 neutropenia

Gr2 fatigue

C8 D8

5-0001 Diarrhea gr1; nasal congestion

gr1; nausea gr1; pain in

C5 D1 Protocol required dose

reduction because MTD

C14 D1

25

extremity gr1; hypernatremia

gr1

exceeded

5-0002

Fever gr1; vomiting gr1;

headache gr1; fatigue gr3;

anemia NOS gr1;

hypothyroidism gr1; AST

elevated gr1; creatinine

elevated gr1;

hyperphosphatemia gr1 ;

hypomagnesemia gr1;

neutropenia gr1; diarrhea gr1

C2 D1 Gr3 fatigue

C15 D1

5-0003

Rash NOS gr1; diarrhea gr1;

alopecia gr1; anorexia gr2;

nausea gr2; vomiting gr1; pain

in extremity gr2;

hyperphosphatemia gr1

N/A N/A

C3 D1

5-0004

Diarrhea gr2; hypocalcemia


hyponatremia gr1; ALK

elevated gr1

N/A N/A

C3 D1

5-0005Abdominal pain gr2, nausea

gr3, vomiting gr3, diarrhea gr3

N/A N/A- did not resume

treatment after DLTC1 D1

5-0006WBC decreased gr2;

neutropenia gr2; dizziness gr1

C3 D1 Gr2 neutropeniaC6 D1

5-0007

Diarrhea gr1; fatigue gr1;

nausea gr 2; constipation gr 1;

pain in extremity gr1; external

ear inflammation gr1

N/A N/A

C14 D1

5-0008

Blurred vision gr2; dyspnea

gr2; rash gr3; papilledema gr3

C2 D1 Gr3 rash and papilledema C1 D1

5-0009Nausea gr2; alopecia gr1 N/A N/A-patient chose to

discontinue treatmentC1 D1

5-0010 Diarrhea gr1; anorexia gr1; C9 D1 Gr2 neutropenia C16 D1

26

nausea gr1; weight loss gr1;

neutropenia gr2; dyspnea gr1;

fatigue gr1; pain in extremity

gr1; mucositis oral gr1;

gastroesophageal reflux

disease gr1

5-0011Diarrhea gr1; fatigue gr1; rash

NOS gr2, nausea gr1

N/A N/AC3 D1

5-0012

Diarrhea gr2; fatigue gr2;

nausea gr2; weight loss gr1;

vomiting gr2

N/A N/A

C3 D1

6-0001 Infusion reaction gr2 N/A N/A C1 P only

6-0002

Mucositis oral gr2; pruritus gr2; rash NOS gr3; PPE gr3; AST elevated gr2; ALT elevated gr2; nausea gr2;

fatigue gr2; peripheral sensory

neuropathy gr1; xerostomia

gr1

C3 D1

C5 D1

C6 D1

Gr3 rash NOSGr3 rash NOSGr2 AST elevated + Gr2 ALT elevated +

Gr3 PPE

C6 D1

6-0003

Myalgia gr1; agitation gr1;

diarrhea gr1; headache gr1;

rash NOS gr3;


hypernatremia gr1

C3 D1 Gr3 rash NOS

C3 D1

6-0004

Pain in extremity gr1; WBC

decreased gr1;


anemia NOS gr2; rash NOS gr2; blurred vision gr1;

dysgeusia g1; pruritus gr3;

mucositis oral gr2

C4 D1 Gr3 pruritus + Gr2 rash

C5 D1

6-0005 Fever gr1; diarrhea gr1;

anxiety gr1; thrombotic event

gr2; skin infection gr2; PPE

C3 D1 Gr2 skin infection C6 D1

27

gr2; insomnia gr1

6-0006

Fatigue gr1; skin infection gr1;

laryngeal inflammation gr 1;

anemia NOS gr1; mucositis

gr2; rash NOS gr2; diarrhea

gr3

N/A N/A

C15 D1

6-0007Nausea gr1; rash gr1;

vomiting gr2; cough gr2

N/A N/AC3 D1

gr-grade; C-cycle; D-day; WBC-white blood cell count, AST-aspartine transaminase; ALT-

alanine transaminase; NOS-not otherwise specified; PPE-palmar plantar dysesthesia; COPD-

chronic obstructive pulmonary disease; ALK-alkaline phosphatase; N/A-not applicable

Shaded cells indicate patients that were enrolled after the amendment mandating

dexamethasone premedication

Bold font-considered a likely or definitely-related immune-related adverse event

28

media.nature.com · web viewif cbc or platelets lead to a -1 dose level reduction per table above,...

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