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6. dose modifications

Individually, each subject will be allowed up to dose-reduce to 75 mg infigratinib, as follows (see also Table 5).  
If a subject's infigratinib dose is 125 mg, 2 dose reductions of infigratinib are permitted.  
If a subject's infigratinib dose is 100 mg, 1 dose reduction of infigratinib is permitted.  
If a subject's infigratinib dose is 75 mg, no dose reduction of infigratinib is permitted, with infigratinib treatment discontinuation the only option.
Subjects should discontinue infigratinib if toxicities persist following dose reductions to the lowest level allowed, unless it has been discussed and approved by the QED Therapeutics' Medical Monitor.  
Following resolution of toxicity to baseline or ≤ Grade 1, or ≤ Grade 2 for hematologic toxicities, treatment is resumed at either the same or lower dose of study drug as per the criteria in Table 6. Adverse event lab abnormalities outlined in Table 6 should be followed at least weekly until the specified resolution. If treatment is resumed at the same dose of study drug, and the same toxicity recurs with the same or worse severity regardless of duration, dose must be reduced to the next lower dose level. If treatment is resumed at the lower dose of study drug, and the same toxicity recurs with the same or worse severity, the subject should have a second dose reduction.  
Subjects who are withdrawn from the study for a study related AE or an abnormal laboratory value must be followed as described in Section 7.3.  
| Dose Reduction   | Dose level 3   | (Starting) Dose level 2   | Dose level 1   |
|------------------|----------------|---------------------------|----------------|
| Infigratinib     | 125 mg         | 100 mg                    | 75 mg          |  
1B
In exceptional situations, study drug may continue even if the subject experienced one of the treatment stopping rules. The decision to allow for continuation of treatment will be made on a case-by-case basis following discussion between QED Therapeutics and the investigator.  
Table 6. Criteria for Interruption and Re-initiation of Infigratinib for AEs Considered to be  
Possibly Related to Infigratinib  
| Possibly Related to Infigratinib                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                                      |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------|
| Worst Toxicity CTCAE (v5.0)  Grade (Unless Otherwise  Specified)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Recommended Dose Modifications any Time During a Cycle of  Therapy CARDIAC DISORDERS |
| Cardiac - Prolonged QTcF Interval Grade 1 and 2: QTcF ≥ 481msec  Maintain dose level of infigratinib.  and ≤ 500 msec (asymptomatic) Two additional ECGs separated by at least 5 minutes should be  performed to confirm the finding. If the finding is confirmed, single  ECG assessments should be performed every 2 weeks for  2 additional cycles, or as clinically indicated. If abnormality is  detected, 2 additional ECGs separated by at least 5 minutes should  be performed to confirm the finding.   If ECG assessments show no QTcF ≥ 481 msec, for subsequent  cycles ECG monitoring will be performed at each subsequent visit,  per visit schedule.   If ECG assessments are still abnormal (QTcF ≥ 481 msec and  ≤ 500 msec), then ECG monitoring must continue every 2 weeks for all subsequent cycles. Grade 3: QTcF > 500msec or  > 60 ms change from baseline as  identified on the ECG by the  investigator Hold infigratinib. Two additional ECGs separated by at least 5  minutes should be performed to confirm the finding. If the finding is  confirmed, the subject should be admitted to the hospital for at least  24 hours of continuous telemetry; once confirmed no further  prolongation of QTc and no arrhythmias over 24 hour period, subject  can be discharged. After discharge, subject should return to clinic  weekly for ECG until normalization.   Exclude other causes of QTcF prolongation such as hypokalemia,  hypomagnesaemia, and decreased blood oxygenation.   Subjects should receive appropriate electrolyte replacement and  should not receive further infigratinib until electrolytes are  documented to be within normal limits.  Once the QTcF prolongation has resolved, subjects may be re-treated  at one lower dose level at the investigator's discretion. |                                                                                      |  
1B  
| Table 6. Criteria for Interruption and Re-initiation of Infigratinib for AEs Considered to be  Possibly Related to Infigratinib   |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        |
|-----------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Worst Toxicity CTCAE (v5.0)  Grade (Unless Otherwise  Specified)                                                                  | Recommended Dose Modifications any Time During a Cycle of  Therapy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |
| Grade 3: QTcF > 500msec or  > 60 ms change from baseline as  identified on the ECG by the  investigator (continued)               | Single ECG assessments should be performed for 2 additional cycles  every 2 weeks or as clinically indicated. If abnormality is detected, 2  additional ECGs separated by at least 5 minutes should be performed  to confirm the finding.   If ECG assessments show no QTcF ≥ 481 msec, ECG monitoring  will be performed at each subsequent visit, per visit schedule for  subsequent cycles.   If ECG assessments are still abnormal (QTcF ≥ 481 msec and  ≤ 500 msec), then ECG monitoring must continue every 2 weeks or  as clinically indicated, for all subsequent cycles.   Subjects who experience recurrent QTcF ≥ 500msec after one  dose reduction will be withdrawn from study.  If QTcF > 500 msec or > 60 msec change from the baseline is  observed, a plasma sample for determination of infigratinib  concentration should be obtained with the time of sample collection  noted. |
| Grade 4: Torsade de pointes or  polymorphic ventricular  tachycardia or signs/symptoms of  serious arrhythmia                     | Discontinue infigratinib.  A plasma sample for determination of infigratinib concentration should  be obtained with the time of sample collection noted.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               |
| Cardiac Disorders - Others Grade ≥ 3 OR Congestive heart                                                                          | Discontinue infigratinib.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              |
| failure Grade ≥ 2                                                                                                                 | INVESTIGATIONS-HEMATOLOGY *                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |
| ANC Decreased (Neutropenia)* Grade 3 (ANC                                                                                         | Hold dose of infigratinib until resolved to CTCAE Grade ≤ 2 or                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         |
| < 1.0 to 0.5 × 109 /L)                                                                                                            | baseline, then  If resolved within ≤ 7 days, maintain dose level of infigratinib  If resolved between > 7 days and 14 days, decrease by 1 dose level of infigratinib  If not resolved within ≤ 14 days, discontinue infigratinib                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |
| Grade 4 (ANC < 0.5 × 109 /L)                                                                                                      | Hold dose of infigratinib until resolved to CTCAE ≤ Grade 2, decrease by 1 dose level of infigratinib  If not resolved within ≤ 14 days, discontinue infigratinib                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     |  
1B
Table 6. Criteria for Interruption and Re-initiation of Infigratinib for AEs Considered to be Possibly Related to Infigratinib  
| Worst Toxicity CTCAE (v5.0)  Grade (Unless Otherwise  Specified)   | Recommended Dose Modifications any Time During a Cycle of  Therapy   |
|--------------------------------------------------------------------|----------------------------------------------------------------------|  
| of Neutropenia": that is, if any of the following risk factors for an infection-associated complication are  present - sepsis syndrome, age > 65 years, ANC < 100/mcL, clinically documented infection, invasive  fungal infection, hospitalization at the time of fever, or prior episode of febrile neutropenia. Grade 3 (ANC < 1.0 × 109 /L,  single temperature of > 38.3°C or  a sustained temperature  of ≥ 38.0°C) Hold dose of infigratinib until resolved to CTCAE Grade ≤ 2, then  If resolved within ≤ 7 days, decrease by 1 dose level of infigratinib.   If not resolved within 7 days, discontinue subject from study drug Grade 4 Discontinue infigratinib.   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Anemia *  
| General Comment: Consider packed RBC transfusion for hemoglobin < 7 g/dL, or < 8 g/dL for subjects  with preexisting cardiovascular disease, per AABB guidelines, or if the investigator suspects the subject is  symptomatic from anemia.  Grade 3 (hemoglobin < 8.0 g/dL) Hold dose of infigratinib until resolved or corrected to CTCAE  Grade ≤ 2 or baseline, then maintain dose level Grade 4 Hold dose of infigratinib until resolved or corrected to CTCAE  Grade ≤ 2 or baseline, then decrease by 1 dose level Platelet Count Decreased (Thrombocytopenia) * Grade 3 (platelet  < 50 to 25 × 109 /L) without  ≥ Grade 2 bleeding Hold dose of infigratinib until resolved to CTCAE Grade ≤ 2 or  baseline  If resolved within ≤ 7 days, maintain dose level of infigratinib  If resolved between > 7 days and 14 days, decrease by 1 dose level of infigratinib  If not resolved within ≤ 14 days, discontinue infigratinib Grade 3 (platelet  < 50 to 25 × 109 /L) with bleeding  or Grade 4 (platelet < 25 × 109 /L) Hold dose of infigratinib until resolved to CTCAE Grade ≤ 2 or  baseline, then decrease by 1 dose level  If not resolved within ≤ 14 days, discontinue infigratinib   |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
1B  
| Table 6. Criteria for Interruption and Re-initiation of Infigratinib for AEs Considered to be  Possibly Related to Infigratinib                                                                     |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Worst Toxicity CTCAE (v5.0)  Grade (Unless Otherwise  Specified)                                                                                                                                    | Recommended Dose Modifications any Time During a Cycle of  Therapy INVESTIGATIONS - RENAL                                                                                                                                                                                                                                                                                                                                                                                         |
| Serum Creatinine Grade ≥ 2                                                                                                                                                                          | If serum creatinine CTCAE Grade ≥ 2 has been demonstrated in  conjunction with hyperphosphatemia, serum creatinine levels must be  repeated at least weekly until resolution. 24-hour urine collection  should be obtained as clinically indicated for total phosphate, calcium,  protein, and creatinine clearance. Ultrasound examination of the  kidneys should be performed as indicated to evaluate de-novo  calcifications until resolution or stabilization of creatinine. |
| Grade 2 (≥ 2.00 to 3.0 × ULN or                                                                                                                                                                     | Hold dose of infigratinib until resolved to Grade ≤ 1 or baseline                                                                                                                                                                                                                                                                                                                                                                                                                 |
| 2.0 to 3.0 × baseline)                                                                                                                                                                              |  If resolved within ≤ 7 days, maintain dose level of infigratinib  If resolved between > 7 days and 14 days, decrease by 1 dose level of infigratinib  If not resolved within ≤ 14 days, discontinue infigratinib                                                                                                                                                                                                                                                              |
| Grade ≥ 3 (> 3.0 × ULN or                                                                                                                                                                           | Discontinue infigratinib                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| > 3 × baseline)                                                                                                                                                                                     | INVESTIGATIONS - HEPATIC                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| AST or ALT Grade 3 (> 5.0 to 20.0 × ULN)  without bilirubin elevation  > 2.0 × ULN                                                                                                                  | Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1 or  baseline  If resolved within ≤ 7 days, decrease by 1 dose level of infigratinib  If not resolved within ≤ 7 days, discontinue infigratinib                                                                                                                                                                                                                                                                      |
| Grade 4 (> 20.0 × ULN) without                                                                                                                                                                      | Discontinue infigratinib                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| bilirubin elevation > 2.0 × ULN AST or ALT and Bilirubin AST or ALT > 3.0 to 5.0 × ULN  and total bilirubin > 2.0 × ULN  without liver metastasis or  evidence of disease progression  in the liver | Hold dose of infigratinib until both transaminases and bilirubin  resolved to CTCAE Grade ≤ 1 or baseline.   If resolved within ≤ 7 days, decrease by 1 dose level of infigratinib.   If not resolved within ≤ 7 days, discontinue infigratinib                                                                                                                                                                                                                                 |
| AST or ALT > 5.0 × ULN and total                                                                                                                                                                    | Discontinue infigratinib                                                                                                                                                                                                                                                                                                                                                                                                                                                          |
| bilirubin > 2.0 × ULN                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   |  
1B  
| Table 6. Criteria for Interruption and Re-initiation of Infigratinib for AEs Considered to be  Possibly Related to Infigratinib                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                    |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|
| Worst Toxicity CTCAE (v5.0)  Grade (Unless Otherwise  Specified)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | Recommended Dose Modifications any Time During a Cycle of  Therapy |
| LABORATORY / METABOLIC DISORDERS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            |                                                                    |
| Asymptomatic Amylase and/or Lipase Elevation General Comment: Assess for symptoms of acute pancreatitis (abdominal pain or tenderness), and, if  present, consider a CT scan or other imaging study to assess the pancreas, liver, and gallbladder to  confirm the diagnosis of acute pancreatitis and assess for complications. Grade 3 (> 2.0 to 5.0 × ULN)  Hold dose of infigratinib until resolved to CTCAE Grade ≤ 2  decrease by 1 dose level of infigratinib  If not resolved within ≤ 14 days, discontinue infigratinib For recurrent Grade 3 asymptomatic lipase or amylase elevation  despite dose reduction, infigratinib should be held and continuation of  therapy should be discussed with the medical monitor following  resolution to ≤ Grade 2. Grade 4 (> 5.0 × ULN) For any Grade 4 asymptomatic lipase or amylase elevation,  infigratinib should be held and continuation of therapy should be  discussed with the medical monitor following resolution to ≤ Grade 2. Hyperphosphatemia Serum phosphorus  Maintain dose level of infigratinib and optimize phosphate lowering  > 5.5 to 7.0 mg/dL therapy (see "Management of Hyperphosphatemia" in Section 4.2). Serum phosphorus > 7.0 mg/dL If serum phosphorus is > 7.0 mg/dL, serum phosphorus should be  monitored every 2 to 3 days until ≤ 7.0 mg/dL.  For serum phosphorus that is > 7.0 mg/dL for more than 7 days, or for  a single serum phosphorus > 9.0 mg/dL:  Hold infigratinib dose until resolved to serum  phosphorus ≤ 5.5 mg/dL.  For serum phosphorus that is > 7.0 mg/dL for more than 7 days:  Restart infigratinib at the same dose level with increased  phosphate binder dosing if the subject did not receive maximal phosphate binder dosing (sevelamer 1600 mg 3 times daily).   Reduce one dose level of infigratinib if the subject had received  maximal phosphate lowering therapy (sevelamer 1600 mg three times daily). Continue maximal phosphate binder dosing.  For serum phosphorus that is > 9.0 mg/dL:  Reduce one dose level of infigratinib. Restart infigratinib with  maximal phosphate binder dosing.  It is recommended that phosphate binder dosing continues during  infigratinib dose interruptions for hyperphosphatemia. |                                                                    |  
1B  
| Table 6. Criteria for Interruption and Re-initiation of Infigratinib for AEs Considered to be  Possibly Related to Infigratinib   |                                                                                                                                                                                                                                                                                                                  |
|-----------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Worst Toxicity CTCAE (v5.0)  Grade (Unless Otherwise  Specified)                                                                  | Recommended Dose Modifications any Time During a Cycle of  Therapy                                                                                                                                                                                                                                               |
| Hypercalcemia Serum calcium Grade 2                                                                                               | Hold infigratinib dose until resolved to Grade 1 or baseline:  If resolved within ≤ 7 days after suspending infigratinib, maintain  dose level  If resolved between > 7 days and 14 days after suspending  infigratinib, decrease by 1 dose level  If not resolved within ≤ 14 days, discontinue infigratinib |
| Serum calcium ≥ Grade 3                                                                                                           | Discontinue subject from study drug NERVOUS SYSTEM DISORDERS                                                                                                                                                                                                                                                     |
| Any Grade 2 neurotoxicity                                                                                                         | Omit dose of infigratinib until resolved to CTCAE Grade ≤ 1, then decrease by 1 dose level of infigratinib  If not resolved within ≤ 14 days, discontinue infigratinib                                                                                                                                          |
| Any Grade ≥ 3 neurotoxicity                                                                                                       | Discontinue infigratinib                                                                                                                                                                                                                                                                                         |
| GASTROINTESTINAL SYSTEM DISORDERS                                                                                                 |                                                                                                                                                                                                                                                                                                                  |
| Pancreatitis Grade ≥ 2                                                                                                            | Discontinue infigratinib                                                                                                                                                                                                                                                                                         |
| Diarrhea General Comment:                                                                                                         | Antidiarrheal medication is recommended at the first sign of  abdominal cramping, loose stools or overt diarrhea                                                                                                                                                                                                 |
| Grade 1                                                                                                                           | Maintain dose level of infigratinib, initiate anti-diarrheal treatment                                                                                                                                                                                                                                           |
| Grade 2                                                                                                                           |  Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1  Optimize anti-diarrheal treatment  For reoccurrence of diarrhea CTCAE Grade 2, hold dose of  infigratinib until resolved to CTCAE Grade ≤ 1, decrease infigratinib by 1 dose level                                                              |
| Grade 3                                                                                                                           |  Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1  Optimize anti-diarrheal treatment  Decrease infigratinib by 1 dose level  For reoccurrence of diarrhea CTCAE Grade 3, despite optimal  antidiarrheal treatment, discontinue infigratinib                                                       |
| Grade 4                                                                                                                           | Discontinue infigratinib                                                                                                                                                                                                                                                                                         |  
1B  
| Possibly Related to Infigratinib                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                    |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------|
| Worst Toxicity CTCAE (v5.0)  Grade (Unless Otherwise  Specified)                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       | Recommended Dose Modifications any Time During a Cycle of  Therapy |
| Vomiting Grade 2 not controlled by optimal                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Hold infigratinib doses until ≤ Grade 1, decrease by 1 dose level  |
| anti-emetic therapy                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    |  If not resolved within ≤ 14 days, discontinue infigratinib       |
| Grade 3 not controlled by optimal                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | Discontinue infigratinib                                           |
| anti-emetic therapy, or Grade 4 EYE DISORDERS (CONFIRMED BY OPHTHALMOLOGIC EXAMINATION) Retinal Disorders Grade 2 central serous  retinopathy and central serous  retinopathy -like events Hold infigratinib until resolved to ≤ Grade 1 and continue  ophthalmologic evaluation  If resolved within ≤ 14 days, decrease infigratinib by 1 dose level  If resolved after > 14 days, discontinue infigratinib Grade ≥ 1 retinal vein occlusion,  Grade 3 or 4 central serous  retinopathy and central serous  retinopathy-like events, and  Grade 3 or 4 other eye disorders Discontinue infigratinib Other Ocular/Visual Toxicity Grade ≥ 3 Discontinue infigratinib  SKIN DISORDERS Palmar-plantar erythrodysesthesia syndrome Grade 3 Hold dose of infigratinib until resolved to Grade ≤ 1, and then resume  infigratinib at decrease by 1 dose level Paronychia Grade 3 Hold dose of infigratinib until resolved to Grade ≤ 1, and then resume  infigratinib at decrease by 1 dose level. Stomatitis Grade 3 Hold dose of infigratinib until resolved to Grade ≤ 1, and then resume  infigratinib at decrease by 1 dose level. Grade 4 Discontinue infigratinib |                                                                    |  
1B  
Table 6. Criteria for Interruption and Re-initiation of Infigratinib for AEs Considered to be  
Possibly Related to Infigratinib  
| Possibly Related to Infigratinib                                                                      |                                                                                                                                                                                         |
|-------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Worst Toxicity CTCAE (v5.0)  Grade (Unless Otherwise  Specified)                                      | Recommended Dose Modifications any Time During a Cycle of  Therapy GENERAL DISORDERS                                                                                                    |
| Fatigue Grade ≥ 3                                                                                     | Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1  If resolved within ≤ 7 days, maintain dose level of infigratinib.   If resolved after > 7 days, discontinue infigratinib |
| OTHER CLINICALLY SIGNIFICANT AEs                                                                      |                                                                                                                                                                                         |
| Grade 3                                                                                               | Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1, then  decrease by 1 dose level of infigratinib  If not resolved within ≤ 14 days, discontinue infigratinib                |
| Grade 4                                                                                               | Discontinue infigratinib                                                                                                                                                                |
| Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, |                                                                                                                                                                                         |  
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST,
aspartate aminotransferase; CT, computed tomography; CTCAE, Common Terminology Criteria for Adverse Events; ECG, electrocardiogram; QTcF, QTc corrected by Fridericia's formula; ULN, upper limit of normal.
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7. adverse events and reporting

Adverse events related to calcium/phosphorous homeostasis are expected and on-target effects of infigratinib. Hyperphosphatemia in particular is a reliable biomarker of pathway inhibition and rapidly normalizes upon drug discontinuation without sequelae. Among 433 subjects treated with infigratinib monotherapy, hyperphosphatemia was seen in 62% and in 7% it was Grade 3 or 4. Adverse events associated with calcium/phosphate imbalance (including soft tissue mineralization or ectopic calcifications) have been rare. There have been 3 suspected unexpected SAEs reported related to calcium/phosphorus homeostasis:
(1) hepatic failure due to lesion calcification occurring over 6 months after study drug discontinuation, (2) one episode of hypercalcemia, and (3) one episode of hypophosphatemia/hypocalcemia.  
Ophthalmologic adverse events may occur with infigratinib, and mandated ophthalmologic examinations have been performed routinely and frequently. Most of these events are Grade 1 or 2: for example, dry eye in 22% and blurry vision in 10%. Grade 3 ocular events have occurred in 3%, and no Grade 4 ocular events have occurred. Grade 3 ocular events included cataract (0.7%), visual impairment (0.5%), and keratitis (0.5%).  
Gastrointestinal adverse events are frequently reported. For subjects treated with monotherapy, the most frequent GI AEs (regardless of relationship to study drug)
were constipation (37%), decreased appetite (30%), nausea (29%), diarrhea (27%),
vomiting (20%), and dyspepsia (15%). Stomatitis was reported in 35%, and in 5%
was Grade 3 or 4.
1B  
Skin, hair, and nail changes are frequently reported. For subjects treated with monotherapy, 27% experienced alopecia, 13% experienced dry skin, and 12% experienced palmar-plantar erythrodysaesthesia syndrome.  
For others, please see Section 2.2 (especially Tables 2 to 4) and the Investigator's Brochure.  
7.1.2 Related to Tamoxifen (Cohort 1) (reported percentages are from N = 3,094 subjects in the ATAC trial)
Hot flashes (64%) (placebo 48%)
Vaginal discharge (30%) (placebo 15%)
Nausea (26%) (placebo 24%)
Fluid retention (32%) (placebo 30%)
Mood disturbances Thrombotic events (0.8% deep vein thrombosis, 0.5% pulmonary embolism, 0.4%
superficial phlebitis)
For others, please see tamoxifen package insert from the FDA.
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7.2 adverse event definitions

An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s),
symptom(s), or medical condition(s). An SAE is defined as one of the following:  
Is fatal or life-threatening Results in persistent or significant disability/incapacity Constitutes a congenital anomaly/birth defect Is medically significant, ie, defined as an event that jeopardizes the subject or may require medical or surgical intervention to prevent one of the outcomes listed above Requires in-patient hospitalization or prolongation of existing hospitalization, unless hospitalization is for: o Routine treatment or monitoring of the studied indication, not associated with any deterioration in condition o Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication under study and has not worsened since signing the informed consent o Treatment on an emergency out-patient basis for an event not fulfilling any of the definitions of a SAE given above and not resulting in hospital admission o Social reasons and respite care in the absence of any deterioration in the subject's general condition
Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or symptoms, are considered clinically significant, require therapy (eg, hematologic abnormality that requires transfusion or hematological stem cell support), or require changes in study drug(s).  
Progression of underlying malignancy is not considered as an AE if it is clearly consistent with the suspected progression of the underlying cancer as defined by RECIST criteria v1.1, or other criteria as determined by protocol. Hospitalization due solely to the progression of underlying malignancy should NOT be reported as an SAE.  
Clinical symptoms of progression may be reported as AEs if the symptom cannot be determined as exclusively due to the progression of the underlying malignancy, or does not fit the expected pattern of progression for the disease under study.  
Symptomatic deterioration may occur in some subjects. In this situation, progression is evident in the subject's clinical symptoms, but is not supported by the tumor measurements. Or, the disease progression is so evident that the investigator may elect not to perform further disease assessments. In such cases, the determination of clinical progression is based on symptomatic deterioration. These determinations should be a rare exception as every effort should be made to document the objective progression of underlying malignancy.  
If there is any uncertainty about an AE being due to progression of the disease under study, it should be reported as an AE or SAE.
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7.3 adverse events reporting

Adverse events (AEs) will be documented and recorded at each scheduled or unscheduled visit, including end-of-treatment and during follow-up, using NCI CTCAE v5.0. Subjects will be followed for AEs for 30 days after the last treatment administration or until all drug-related toxicities have resolved (or the Investigator determines in his/her clinical judgment that no further improvement is expected), whichever is later. For serious adverse events (SAEs), the active reporting period will be from the time that the subject provides informed consent, which is obtained prior to the subject's participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 30 calendar days after the last administration of the investigational product. SAEs experienced by a subject after the active reporting period has ended should be reported if the Investigator becomes aware of them. Conditions already present at the time of informed consent should be recorded in the Medical History CRF.  
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis whenever possible, rather than individual underlying signs and symptoms. When a clear diagnosis cannot be identified, each sign or symptom should be reported as a separate AE.  
The following information is to be captured in the CRF for each AE: severity grade (CTCAE v5.0, Grade 1 to 5); duration (start and end dates); relationship to study drug
(infigratinib or tamoxifen) (reasonable possibility that AE is related: No, Yes); action taken with respect to study drug (none, dose reduction, temporarily interrupted, permanently discontinued, unknown, not applicable); whether medication or therapy was given (no concomitant medication/non-drug therapy given, concomitant medication/non-drug therapy given); outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, recovered/resolved with sequelae, fatal, unknown); and whether the event is serious and seriousness criteria.
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7.4 reporting serious adverse events

Every SAE, regardless of suspected causality, occurring after the subject has signed informed consent through 30 days after the subject has taken his/her last dose of study drug, will be 1B
reported to the Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study-specific CRF, and to Helsinn Healthcare SA by email (drug-safety@helsinn.com) using their provided CRFs, within 24 hours of learning of its occurrence. Following review by the Stanford DSMC, events meeting the IRB definition of 'Unanticipated Problem' will be reported to the IRB using eProtocol within 10 working days of DSMC review, or within 5 working days for deaths or life-threatening experiences. Any SAEs experienced after this 30-day period should only be reported to the DSMC if the investigator suspects a causal relationship to the study drug. Any additional information for the SAE including recurrent episodes, complications, or progression of the initial SAE must be reported as follow-up to the original episode within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a different time interval or otherwise considered completely unrelated to a previously reported one should be reported separately as a new event. Follow-up information is submitted in the same way as the original SAE Report. Each reoccurrence, complication, or progression of the original event should be reported as a follow-up to that event regardless of when it occurs. The follow-up information should describe whether the event has resolved or continues, if and how it was treated, and whether the subject continued or withdrew from study participation.  
If the SAE is not an expected event as per the current Investigator's Brochure or Package Insert
(new occurrence or increased frequency) and is thought to be related to the study drug (a Suspected Unexpected Serious Adverse Reaction, "SUSAR"), it must also be reported to Helsinn Healthcare SA via email (drug-safety@helsinn.com) using their provided CRFs within 24 hours of learning of the event and to the FDA via an IND Safety Report within 15 days
(7 days if life-threatening or death). QED Therapeutics and partner, the Helsinn Group, will be responsible to send investigator notifications to investigators involved with infigratinib studies.
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7.5 pregnancy

Female subjects must be discontinued from study drug in the event of pregnancy.  
To ensure subject safety, each pregnancy of a subject or partner of a male subject occurring while the subject is on study drug must be reported to the Stanford DSMC and Helsinn Healthcare SA (via email at drug-safety@helsinn.com) using their provided CRFs within 24 hours of learning of its occurrence.  
For Stanford DSMC reporting, the pregnancy should be followed up to determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. Consent to report information regarding pregnancy and pregnancy outcomes should be obtained from the partner of the male subject. Pregnancy of a subject or partner of a male subject should be recorded on a Pregnancy Notification Form and entered on the Pregnancy eCRF. Pregnancy follow-up should be recorded and include an assessment of the possible relationship to the study drug of any pregnancy outcome. Pregnancy and pregnancy follow-up should be reported to the Stanford DSMC and Helsinn Healthcare SA (via email at drug-safety@helsinn.com) using their provided CRFs.
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8. correlative/special studies

Two types of specimens, tumor tissues and plasma, will be collected for correlative studies.
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8.1 laboratory correlative studies 8.1.1

Fresh tumor tissue will be collected on subjects participating in the study during the pre-treatment and on-treatment research biopsies, which are mandatory if deemed safe and feasible by the investigator. Procedures will be done according to best clinical practice guidelines as are all procedures at Stanford Hospital. Four to eight research-specific core biopsies will be taken, depending on the biopsy site and investigator assessment of safety and feasibility. Research biopsies will not be taken if there is felt to be more than minimal additional risk. Details on processing of specimens are provided in the lab manual.
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8.1.1.2 coding of specimens for

Study staff (eg, the protocol director or clinical research coordinator) will create a unique anonymous identifier for each specimen at time of subject data collection and entry into the secure REDCap database. The unique anonymized identifier will be assigned sequentially within each cohort (eg, INF1001, INF1002, etc; INF2001, INF2002, etc). All tissue specimens will be labeled with this anonymous identifier and no subject-identifiable information. The link between anonymous identifier and subject information will be stored in the secure REDCap database.
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8.1.2 plasma collection and processing

20 cc of blood will be collected in black and tan top Streck Cell-Free DNA BCT tubes at screening or on Cycle 1 Day 1, on Cycle 1 Day 15 (± 3 days), and then again at End of Treatment. Details on processing of specimens are provided in the lab manual.
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8.1.2.2 coding of specimens for

As with the tissue specimens (Section 8.1.1), plasma specimens will be labeled with the same anonymous identifier and no subject-identifiable information. The link between anonymous identifier and subject information will be stored in the secure REDCap database.  
1B
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9. study calendar

| 9. STUDY CALENDAR                                                                      | Screening                    | On Treatment (1 Cycle = 28 days)       | Post-Treatment             |                    |        |       |    |     |     |
|----------------------------------------------------------------------------------------|------------------------------|----------------------------------------|----------------------------|--------------------|--------|-------|----|-----|-----|
| (Within                                                                                | Cycle 1                      | Cycle 2                                | Cycles  3                 | End of Treatment / |        |       |    |     |     |
| withdrawal (0 to 14 days  from decision to  discontinue) 23                            | 30-day                       |                                        |                            |                    |        |       |    |     |     |
| 21 days of                                                                             | Follow-up                    |                                        |                            |                    |        |       |    |     |     |
| Cycle 1,                                                                               | Day 1                        | Day 4                                  | Day 15                     | Day 1              | Day 15 | Other |    |     |     |
| (± 3 days) (± 1 day) (± 3 days) (± 3 days) (± 3 days)                                  | Day 1 (± 3 days)             | (+ 7 days) 24 Follow-up25 Safety Visit |                            |                    |        |       |    |     |     |
| Protocol Activity                                                                      | Day 0)                       |                                        |                            |                    |        |       |    |     |     |
| Informed Consent 1                                                                     | X                            |                                        |                            |                    |        |       |    |     |     |
| Medical/Tumor History 2                                                                | X                            |                                        |                            |                    |        |       |    |     |     |
| Physical Examination (within  24 hours prior to start of each                          | X                            | X                                      | X                          | X                  | X      | X     | X  | (X) |     |
| cycle)3 ECOG Performance Status 4                                                      | X                            | X                                      | X                          | X                  | X      | X     | X  | (X) |     |
| Safety Labs/Measurements Vital Signs (within 24 hours  prior to start of each cycle) 5 | X                            | X                                      | X                          | X                  | X      | X     | X  | (X) |     |
| Hematology (CBC, differential,  platelets) 6                                           | X                            | X                                      | X                          | X                  | X      | X     | X  | (X) |     |
| Complete metabolic panel 7                                                             | X                            | X                                      | X                          | X                  | X      | X     | X  | X   | (X) |
| Amylase, lipase 8                                                                      | X                            | X                                      | X                          | X                  | X      | X     | X  | (X) |     |
| Calcium, magnesium,  phosphorus 9                                                      | X                            | X                                      | X                          | X                  | X      | X     | X  | X   | (X) |
| Urinalysis 10                                                                          | X                            |                                        |                            |                    |        |       |    |     |     |
| Pregnancy Test 11                                                                      | X                            | X                                      | X                          |                    |        |       |    |     |     |
| Electrocardiogram 12                                                                   | X                            | X                                      | C4D1, C6D1 (± 7 days) then | X                  |        |       |    |     |     |
| every 6 cycles (all ± 14 days)                                                         |                              |                                        |                            |                    |        |       |    |     |     |
| Transthoracic echocardiogram 13                                                        | X                            | X                                      | X                          |                    |        |       |    |     |     |
| X ± 7 da                                                                               | C3D1, C4D1, C6D1 (± 7 days), |                                        |                            |                    |        |       |    |     |     |
| Ophthalmology evaluation 14                                                            | X                            | then every 3 cycles (± 14 days)        | X                          |                    |        |       |    |     |     |
| ys                                                                                     |                              |                                        |                            |                    |        |       |    |     |     |  
| A Phase 1B Study of Infigratinib in Combination with Tamoxifen in Hormone Receptor-positive, HER2-negative, FGFR-altered Advanced Breast Cancer Screening On Treatment (1 Cycle = 28 days)   | Post-Treatment              |                                                |              |                    |        |       |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------|------------------------------------------------|--------------|--------------------|--------|-------|
| (Within                                                                                                                                                                                      | Cycle 1                     | Cycle 2                                        | Cycles  3   | End of Treatment / |        |       |
| withdrawal (0 to 14 days  from decision to  discontinue) 23                                                                                                                                  | 30-day                      |                                                |              |                    |        |       |
| 21 days of                                                                                                                                                                                   | Follow-up                   |                                                |              |                    |        |       |
| Cycle 1,                                                                                                                                                                                     | Day 1                       | Day 4                                          | Day 15       | Day 1              | Day 15 | Other |
| (± 3 days) (± 1 day) (± 3 days) (± 3 days) (± 3 days)                                                                                                                                        | Day 1 (± 3 days)            | (+ 7 days) 24 Follow-up25 Safety Visit         |              |                    |        |       |
| Protocol Activity                                                                                                                                                                            | Day 0)                      |                                                |              |                    |        |       |
|  7 days bef                                                                                                                                                                                 |                             |                                                |              |                    |        |       |
| Registration 1                                                                                                                                                                               | Cycle 1,  Day 1             |                                                |              |                    |        |       |
| Treatment                                                                                                                                                                                    | Daily as 3 weeks on /       |                                                |              |                    |        |       |
| Infigratinib administration 15                                                                                                                                                               | 1 week off for entire cycle | 3 weeks on /                                   | 3 weeks on / |                    |        |       |
| 1 week off                                                                                                                                                                                   | 1 week off                  |                                                |              |                    |        |       |
| Cohort 1: Tamoxifen  administration 16                                                                                                                                                       | Continuous                  | Continuous                                     | Continuous   |                    |        |       |
| Tumor Assessment CT (chest, abdomen, pelvis) 17                                                                                                                                              | X                           | C3D1 (+7 days), then every  2 cycle (± 7 days) | (X)          |                    |        |       |
| Plasma collection 18                                                                                                                                                                         | X                           | X                                              | X            |                    |        |       |
| Research tumor biopsy 19                                                                                                                                                                     | X                           | X                                              |              |                    |        |       |
| Tumor sequencing 20                                                                                                                                                                          | X                           |                                                |              |                    |        |       |
| Other Clinical Assessment Adverse event assessment 21                                                                                                                                        | X                           | Monitor and record at every study visit        | X            | X                  | X      |       |
| Concomitant medications 22                                                                                                                                                                   | X                           | Monitor and record at every study visit        | X            | X                  |        |       |
| 1. Informed Consent: Must be obtained prior to undergoing any study specific procedure and may occur prior to the 21-day screening period. Registration will considered to be                |                             |                                                |              |                    |        |       |  
1. Informed Consent: Must be obtained prior to undergoing any study specific procedure and may occur prior to the 21-day screening period. Registration will considered to be signed informed consent with triple-signed eligibility checklist, with the final signature being the Stanford Principal Investigator or his/her designee.  
2. Medical History / Tumor History: To be collected within 21 days prior to C1D1. Includes history of other diseases (active or resolved) and concomitant illnesses. Oncology history includes information on prior regimens (including dosing and duration of administration, description of best response observed, recurrence date), surgery and radiation therapy. It also includes review of the predicted integrative subtype from FoundationOne. These assays may also be done during screening, as indicated (see footnote 22, "Tumor sequencing"). 3. Physical Examination: Includes an examination of major body systems. Weight for the purposes of dose calculation will be recorded at screening and within 7 days pre-dose Day 1 of each cycle. Weight will also be collected at End of Treatment. Height will be measured at baseline. 1B 4. ECOG Performance Status:
Score **Definition**
0 Fully active, able to carry on all pre-disease activities without restriction 1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, eg, light house work or office work 2 Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours 3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 5 Dead 5. Vital signs: Blood pressure, pulse rate, and body temperature to be recorded in the same position, either supine or sitting. 6. Hematology: No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date. On treatment, to be performed prior to dosing with study medications unless otherwise indicated. Lab abnormalities that are adverse events specified in Table 6 must be followed at least weekly until resolution to the grade specified in Table 6. 7. Complete metabolic panel: No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date. Lab abnormalities that are adverse events specified in Table 6 must be followed at least weekly until resolution to the grade specified in Table 6. 8. Amylase, lipase: No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date. Lab abnormalities that are adverse events specified in Table 6 must be followed at least weekly until resolution to the grade specified in Table 6.  
9. Calcium, magnesium, phosphorus **(serum):** No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date. Lab abnormalities that are adverse events specified in Table 6 must be followed at least weekly until resolution to the grade specified in Table 6. 10. Urinalysis: Macroscopic or microscopic. 11. Pregnancy Test: For female subjects of childbearing potential, a serum or urine pregnancy test must be performed within 7 days of first day of study drug and at end-of-treatment. Additional pregnancy test to be repeated when potential pregnancy is suspected. 12. Electrocardiogram: 12-lead ECG to be performed during Screening, at Cycle 2 Day 1 (± 3 days), Cycle 4 Day 1 (± 7 days), Cycle 6 Day 1 (± 7 days), and then every 6 cycles (± 14 days), and at End-of-Treatment. Additional assessments should be conducted as clinically indicated. 13. Echocardiogram: Transthoracic echocardiogram to be performed during Screening, at Cycle 2 Day 1 (± 3 days), and at End-of-Treatment. Additional assessments should be conducted as clinically indicated. 14. Ophthalmology evaluation: Ophthalmologic examination will be performed by an ophthalmologist during Screening, on Day 1 (± 7 days) of Cycles 2, 3, 4 and 6; then every 3 cycles (± 14 days); and at End-of-Treatment, as well as urgently with any new onset of visual symptoms. These assessments will include visual acuity testing, slit lamp examination of the anterior eye segment, intraocular pressure, dilated fundoscopy, and retinal optical coherence tomography (OCT). Additional examinations such as specular microscopy (that enables a magnified, direct view of the corneal epithelium) and corneal pachymetry will be performed as clinically indicated. 15. Infigratinib Administration: One cycle of infigratinib will be provided to subjects at the beginning of each cycle. Starting dose level of infigratinib for individual subjects will be as defined by study protocol, and may be either 125 mg; 100 mg; or 75 mg infigratinib, each dose level administered as 3 weeks on, 1 week off for every 28-day cycle. 16. Tamoxifen Administration: In Cohort 1, tamoxifen will be prescribed to subjects and will be started at 4 to 8 hours after the administration of infigratinib, starting on Cycle 1 Day 1. Dose is tamoxifen 20 mg/day by mouth continuously. 17. Tumor assessment by imaging: Baseline CT imaging can be done within 28 days prior to C1D1 (versus 21 days for all other baseline/screening assessments). Assessment of response will be made using RECIST v1.1. Antitumor activity will be assessed through radiological tumor assessments conducted at baseline, on treatment every 8 weeks and whenever disease progression is suspected (eg, symptomatic deterioration). After 12 months of therapy, imaging can be spaced out to every 12 weeks at the Investigator's discretion. To be repeated at End of Treatment/Withdrawal only if not done in the previous 4 weeks. Confirmation of response (CR/PR) should be done at least 4 weeks after the initial response. The allowable time window for disease assessments is ± 7 days, on treatment, starting from C1D1, except for the first post baseline assessment (+ 7-day window allowed). Timing should follow calendar days and should not be adjusted for delays in cycle starts. 1B 18. Plasma collection: Two Streck tubes will be collected on Cycle 1 Day 1 prior to study drug initiation, on Cycle 1 Day 15 (± 3 days), and at End of Treatment. Buffy coat separated from the same blood collection will be used for tumor-normal sequencing. 19. Tumor biopsy: A pre-treatment and on-treatment tumor biopsy is mandatory if deemed safe (not posing more than minimal additional risk) and feasible by the investigator. The on-treatment tumor biopsy is recommended to be performed on or around Day 15 of therapy, but can be performed at any time on therapy per protocol. 20. Tumor sequencing: If a potential subject has not had FoundationOne tumor sequencing performed, allowing assessment of predicted integrative subtype, this assay may be sent to determine eligibility. 21. Adverse event **assessments:** Adverse events (AEs) will be documented and recorded at each scheduled or unscheduled visit, including end-of-treatment and during follow-up, using NCI CTCAE v5.0. Subjects will be followed for AEs for 30 days after the last treatment administration or until all drug-related toxicities have resolved (or the Investigator determines in his/her clinical judgment that no further improvement is expected), whichever is later. For serious adverse events (SAEs), the active reporting period will be from the time that the subject provides informed consent, which is obtained prior to the subject's participation in the study, ie, prior to undergoing any study-related procedure and/or receiving investigational product, through and including 30 calendar days after the last administration of the investigational product. SAEs experienced by a subject after the active reporting period has ended should be reported if the Investigator becomes aware of them. The reporting period for non-serious AEs will be from the time the subject has taken at least one dose of study treatment through Day 30 after last dose. If a subject begins a new anticancer therapy, the AE reporting period for non-serious AEs will end at the time the new treatment is started. 22. Concomitant medications: Concomitant medications will be recorded from 30 days prior to the start of study treatment through 30 days after the last dose of study treatment. Concomitant medications will be collected at each scheduled or unscheduled visit, including at end-of-treatment. All concomitant medications should be recorded in the CRF
including supportive care drugs (eg, anti-emetic treatment and prophylaxis), herbal supplements or vitamins, the drugs used to treat adverse events or chronic diseases, and non-drug supportive interventions (eg, transfusions). 23. End of Treatment: To be performed 0 to 14 days after the decision made to discontinue study drug. Obtain these assessments if not completed during the previous week on study. CT scan should be performed at End of Treatment unless CT scan was performed within the previous 4 weeks. 24. 30-Day Follow-Up Safety Visit: Performed 30 to 37 days after last dose of study drug. Information related to concomitant medications and adverse events will be collected for 30 days after the last dose of the study drug. 25. Follow-Up: Subjects continuing to experience toxicity following discontinuation of study treatment will continue to be followed including for adverse events, at least every week (± 3 days) for 4 weeks, and subsequently every 4 weeks (± 7 days), until resolution or determination, in the clinical judgment of the Investigator, that no further improvement is expected. If a follow-up is required beyond 30 to 37 days after last dose of study drug, not all assessments need to be performed. Only assessments that are clinically indicated are necessary for this timepoint.
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10. measurements 10.1 primary endpoint

The primary endpoint is the incidence of dose-limiting toxicities (DLTs) in the first 2 cycles of therapy at a specific dose. In Cohort 1, in a subset of subjects who start at infigratinib 100 mg and complete 2 cycles with no DLTs and who remain on study for Cycles 3 and 4, the dose of infigratinib will be increased to 125 mg starting with Cycle 3 and the number of DLTs in Cycles 3 and 4 will be counted toward the primary endpoint (for the 125 mg dose), in addition to the number of DLTs in Cycles 1 and 2 (for the 100 mg dose). For all other subjects, the primary endpoint will be the number of DLTs in Cycles 1 and 2. DLTs will be graded using NCI CTCAE (Common Terminology Criteria for Adverse Events), v5.0. DLTs will be defined as an adverse event (AE) or abnormal laboratory value at least possibly related to therapy with infigratinib including those AEs and abnormal laboratory values that result in a failure to meet the criteria for re-treatment. The criteria for defining a DLT, which are pre-specified based on the pre-clinical toxicity of infigratinib, are listed in Table 7. Individual subjects who had a DLT may be retreated, after recovery, at the next lowest dose level. Investigators will notify QED Therapeutics within 7 days of any DLTs observed.  
| Table 7. Criteria for defining dose-limiting toxicities                                                                                                 |                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                         |
|---------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------|
| TOXICITY                                                                                                                                                | DLT CRITERION                                                                                                                                                                                                                                                                                                                                                                                                                                           |                                                                         |
| Skipped/                                                                                                                                                | The inability to administer infigratinib on ≥ 75% of scheduled treatment days                                                                                                                                                                                                                                                                                                                                                                           |                                                                         |
| delayed dose                                                                                                                                            | during cycle 1 at that dose (ie, ≥ 16 days of the 21 days of planned treatment) due  to unresolved adverse event of any grade and considered at least possibly,  probably, or definitely related to the study drug.  Delay in 2 nd cycle administration at that dose due to failure of recovery from a  possibly, probably, or definitely related adverse event to Grade ≤ 1 or baseline by  Day 43 (Day 28 of Cycle 1 + 15 days), except for alopecia. |                                                                         |
| Blood/ bone                                                                                                                                             | Neutropenia                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                         |
| marrow                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                                                                                                         | - Febrile, CTCAE Grade ≥ 3.                                             |
|                                                                                                                                                         | - CTCAE Grade ≥ 3 for > 7 consecutive days                                                                                                                                                                                                                                                                                                                                                                                                              |                                                                         |
| Thrombocytopenia  - CTCAE Grade 3 for > 7 consecutive days and/or with signs of  clinically significant bleeding.  - CTCAE Grade 4 Anemia CTCAE Grade 4 |                                                                                                                                                                                                                                                                                                                                                                                                                                                         |                                                                         |
| Renal/                                                                                                                                                  | Creatinine:                                                                                                                                                                                                                                                                                                                                                                                                                                             |                                                                         |
| genitourinary                                                                                                                                           |                                                                                                                                                                                                                                                                                                                                                                                                                                                         | - CTCAE Grade 1 for > 7 consecutive days and serum inorganic phosphorus |
|                                                                                                                                                         | > 5.5 mg/dL and/or serum total calcium x serum inorganic phosphorus                                                                                                                                                                                                                                                                                                                                                                                     |                                                                         |
|                                                                                                                                                         | > 55 mg2 /dL2 and despite phosphorus lowering therapy for ≥ 14 days                                                                                                                                                                                                                                                                                                                                                                                     |                                                                         |
|                                                                                                                                                         | - CTCAE Grade 2 for > 7 consecutive days                                                                                                                                                                                                                                                                                                                                                                                                                |                                                                         |
|                                                                                                                                                         | - CTCAE Grade ≥ 3                                                                                                                                                                                                                                                                                                                                                                                                                                       |                                                                         |  
| Table 7. Criteria for defining dose-limiting toxicities                                                               |                                                                                                                                                                                                                                                                                                                                                         |                                                                           |
|-----------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------|
| TOXICITY                                                                                                              | DLT CRITERION                                                                                                                                                                                                                                                                                                                                           |                                                                           |
| Hepatic                                                                                                               | Bilirubin:  - CTCAE Grade 2 for > 7 consecutive days  - CTCAE Grade ≥ 3 AST or ALT:  - Grade 3 for > 7 consecutive days  - CTCAE Grade 4 Hy's Law  - ALT or AST ≥ 3 x upper limit of normal (ULN)  AND  - Serum total bilirubin > 2 x ULN For patients with known hepatic metastases:  - AST or ALT > 8 x ULN  OR  - AST or ALT > 5 x ULN for ≥ 14 days |                                                                           |
| Pancreas                                                                                                              | Pancreatitis CTCAE Grade ≥ 2 Amylase/lipase (serum-high): CTCAE Grade ≥ 3 asymptomatic amylase and/or   asymptomatic lipase not reversible to CTCAE Grade ≤ 2 within 7 days                                                                                                                                                                             |                                                                           |
| Cardiac                                                                                                               | QTcF interval > 500ms Other cardiac CTCAE Grade ≥ 3                                                                                                                                                                                                                                                                                                     |                                                                           |
| Constitutional                                                                                                        | Fatigue CTCAE Grade 3 for > 7 consecutive days Fatigue CTCAE Grade 4                                                                                                                                                                                                                                                                                    |                                                                           |
| Ocular/visual                                                                                                         | Any ocular/visual toxicity CTCAE Grade ≥ 3.                                                                                                                                                                                                                                                                                                             |                                                                           |
| Gastrointestinal                                                                                                      | CTCAE Grade 3 or 4 nausea/vomiting and/or diarrhea despite the use anti-emetic  and anti-diarrhea therapy, respectively                                                                                                                                                                                                                                 |                                                                           |
| Metabolic/                                                                                                            | Hyperphosphatemia (serum-high):                                                                                                                                                                                                                                                                                                                         |                                                                           |
| laboratory                                                                                                            |                                                                                                                                                                                                                                                                                                                                                         | - Serum inorganic phosphorus > 7.0 mg/dL for > 7 consecutive days despite |
|                                                                                                                       | phosphorus-lowering therapy for at least 14 days.                                                                                                                                                                                                                                                                                                       |                                                                           |
|                                                                                                                       | - Serum inorganic phosphorus > 9.0 mg/dL, despite phosphorus-lowering                                                                                                                                                                                                                                                                                   |                                                                           |
|                                                                                                                       | therapy for at least 14 days.                                                                                                                                                                                                                                                                                                                           |                                                                           |
|                                                                                                                       | - Serum inorganic phosphorus > 10.0 mg/dL                                                                                                                                                                                                                                                                                                               |                                                                           |
| Hypercalcemia (serum-high)  - Serum calcium CTCAE Grade 2 for > 7 consecutive days.  - Serum calcium CTCAE Grade ≥ 3. |                                                                                                                                                                                                                                                                                                                                                         |                                                                           |
| Other                                                                                                                 | Any death not clearly due to the underlying disease or known, extraneous causes. Clinical evidence for any grade (CTCAE Grade ≥ 1) of ectopic, de-novocalcification within the soft tissue including the peri-articular spaces and vascular  as well as visceral tissues (eg, kidney, lung, stomach, myocardium, etc.) Any other CTCAE Grade 3 or 4 non-hematological toxicity except with following  exclusions:  - Alkaline phosphatase CTCAE Grade ≥ 3.  - Lymphocytopenia CTCAE Grade ≥ 3 unless considered clinically significant.                                                                                                                                                                                                                                                                                                                                                         |                                                                           |
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10.2 secondary endpoints

1. Incidence of treatment-emergent adverse events (TEAE). A TEAE is defined as an adverse event with initial onset or increasing in severity after the first dose of study treatment until 30 days after last dose of study drug. TEAEs will be assessed and documented at each scheduled or unscheduled visit during the reporting period. Each TEAE will be assessed according to whether it is serious or non-serious, whether it is expected or unexpected according to the Investigator's Brochure, and whether it is related or unrelated to the study treatment. Each TEAE will be assigned a grade according to CTCAE v5.0. A serious adverse event is one that results in death, is life-threatening, requires in-patient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, may have caused a congenital anomaly/birth defect, or requires intervention to prevent permanent impairment or damage. Pregnancy during the reporting period will be classified as a serious adverse event.  
2. Objective tumor response, per RECIST v1.1 (see Appendix C), in subjects with measurable disease. An objective tumor response can be observed at any time on study between 8 weeks after starting therapy (C3D1) through 18 months after starting therapy.  
3. Progression-free survival (PFS), defined as the number of days to either progressive disease as defined per RECIST v1.1 or death.  
4. Clinical benefit, defined as an objective tumor response or stable disease at 6 months, defined per RECIST v1.1 (see Appendix C).
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10.2.1 measurement methods

For those subjects with bone-only disease, RECIST v1.1 criteria will not be used to assess response. Subjects will stop study drug at when disease is deemed by the investigator to have progressed. 10.2.2 Measurement Time Points Antitumor activity will be assessed through radiological tumor assessments conducted at baseline, on treatment every 8 weeks (± 7 days), and whenever disease progression is suspected (eg, symptomatic deterioration). After 12 months of therapy, imaging can be spaced out to every 12 weeks (± 7 days) at the Investigator's discretion. Studies will be repeated at End of Treatment/Withdrawal only if not done in the previous 4 weeks. Confirmation of response (CR/PR) should be done at least 4 weeks after the initial response. Timing should follow calendar days (starting from C1D1) and should not be adjusted for delays in cycle starts.
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10.3.1 primary outcome primary outcome

Primary Outcome Measure Description: The primary outcome for this study is dose-limiting toxicities (DLTs) during the first 2 cycles of therapy at a specific dose. All grades per the Common Terminology Criteria for Adverse Events (CTCAE). DLT is defined as a related and clinically-significant adverse event (AE), including missed doses due to a related AE. Due to limited number of characters that can present in this field, it is not possible to consistently provide additional details across all sub-elements of this outcome.  
See protocol. The outcome is expressed as the number of DLT events by the assigned infigratinib dose level, a number without dispersion.
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1. outcome title treatment-emergent adverse

Outcome Measure Description: Treatment-emergent adverse events (TEAEs) are defined as adverse events of any grade with initial onset or increasing in severity after the first dose of study treatment until 30 days after last dose of study drug. Pregnancy during the reporting period will be classified as a serious adverse event. The outcome will be expressed as the number of events by the infigratinib dose level at the time of the event, stratified by relatedness and Common Terminology Criteria for Adverse Events
(CTCAE) grade. The result is a number without dispersion.
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time frame 2 years 2.

Outcome Measure Description: Objective tumor response will be assessed as achieving a Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Complete Response (CR) or a Partial Response (PR). The outcome will be reported as the number of subjects by each participant's final infigratinib dose level that achieve an overall response (OR) to treatment, ie, CR or PR, within 18 months of starting treatment.  
The outcome will be reported as a number without dispersion. RECIST criteria are:
- CR = Disappearance of all target lesions
- PR = ≥ 30% decrease in the sum of the longest diameter of target lesions
- Overall Response (OR) = CR + PR - Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s)
- Stable disease (SD) = Small changes that do not meet any of the above criteria Time Frame: up to 18 months 3. **Outcome Title**: Progression-free Survival (PFS)
Outcome Measure **Description**: Progression-free survival (PFS) means the subject is alive without return or relapse of the tumor. The outcome is defined as the number of 1B
days to either progressive disease as defined per RECIST v1.1 or death, by each participant's final infigratinib dose level, and reported as the median PFS with full range.  
RECIST criteria are:
- CR = Disappearance of all target lesions
- PR = ≥ 30% decrease in the sum of the longest diameter of target lesions
- Overall Response (OR) = CR + PR - Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s)
- Stable disease (SD) = Small changes that do not meet any of the above criteria
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time frame up to 2

Outcome Measure Description: Clinical benefit will be assessed as achieving a Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Complete Response (CR) ;
Partial Response (PR); or Stable Disease (SD). The outcome will be reported as the number of subjects by each participant's final infigratinib dose level that achieve a CR;
PR; or SD, within 6 months of starting treatment. The outcome will be reported by treatment and dose level as a number without dispersion. RECIST criteria are: - CR = Disappearance of all target lesions
- PR = ≥ 30% decrease in the sum of the longest diameter of target lesions
- SD = Small changes that do not meet any of the above criteria - Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s)
- SD = Small changes that do not meet any of the above criteria Time Frame: up to 6 months
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11. regulatory considerations 11.1 institutional

This study will be conducted under IND 147595 for infigratinib (pre-assigned). Infigratinib was approved by FDA as Truseltiq pursuant the Accelerated Approval regulations on 28 May 2021 for the indication of previously-treated, unresectable, locally-advanced or metastatic cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement, in adults The protocol, the proposed informed consent and all forms of subject information related to the study (eg, advertisements used to recruit subjects) will be reviewed and approved by the Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC). Any changes made to the protocol will be submitted as a modification and will be approved by the IRB prior to implementation. The Protocol Director will disseminate the protocol amendment information to all participating investigators.
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11.2 data sharing with collaborators

Distributor QED Therapeutics expects to share data from this study with the Helsinn Group (collaborator/partner).
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11.3 data and safety monitoring

The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the monitoring entity for this study. The DSMC will audit study-related activities to determine whether the study has been conducted in accordance with the protocol, local standard operating procedures, FDA regulations, and Good Clinical Practice (GCP). This may include review of the following types of documents participating in the study: regulatory binders, case report forms, eligibility checklists, and source documents. In addition, the DSMC will regularly review serious adverse events and protocol deviations associated with the research to ensure the protection of human subjects. Results of the DSMC audit will be communicated to the IRB and the appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as needed.
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11.4 data management plan

The Protocol Director, or designee, will prepare and maintain adequate and accurate subject case histories with observations and data pertinent to the study. Study specific Case Report Forms (CRFs) will document treatment outcomes for data analysis. Case report forms will be created in the Stanford Research Electronic Data Capture (REDCap) and will be maintained by the Protocol Director, co-Protocol Director, and clinical research coordinator team. All subjects will be registered in the OnCore database, allowing the Stanford SRC to judge the aggregate accrual and stopping rules for the study.
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12. statistical considerations 12.1 statistical

Statistical analyses of this non-randomized, phase 1B study will be primarily descriptive in nature. Formal statistical methods will not be used to determine the number of subjects per cohort/dose level in this phase 1B study. Summary statistics for discrete variables will be provided as frequencies and for continuous variables as the mean, standard deviation, median, and ranges. Cohort 1 will utilize the combination of tamoxifen and infigratinib at 3 infigratinib dose levels (125 mg; 100 mg; and 75 mg). This combination may play a role in the future development of infigratinib for hormone receptor-positive breast cancer, necessitating the establishment of their safety. For example, tamoxifen and infigratinib might be used in the early-stage, (neo)adjuvant setting as well as the late-stage, metastatic setting. Therefore, the design is based on patient resources and current drug development.
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12.2 interim analyses

There will be no additional statistical stopping rules other than the 3+3 design rule for Cohort 1 as described in Section 2.5, and there will be no planned interim analysis.
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12.3 descriptive statistics and exploratory

The exploratory elements described in Section 1.3 will be included in the descriptive statistics and exploratory data analyses.
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12.4 primary safety analysis

Cohort 1 (infigratinib plus tamoxifen) will follow the 3+3 design evaluating 3 infigratinib doses levels, starting at 100 mg infigratinib 3 weeks on/1 week off) and moving to, if needed, 75 mg or 125 mg infigratinib 3 weeks on/1 week off. Given the nature of this cohort to be a safety run-in and the limited number of available subjects for this population, intra-subject dose-escalation will be allowed. The risk with intra-subject dose-escalation is that a dose may be declared overly toxic when the toxicities should be attributed to the number of cycles rather than the dose, but it is believed this is a conservative approach focused on subject safety.  
Initially, 3 subjects will be treated at 100 mg for 2 cycles. If there are no DLTs observed in a subject at 100 mg after 2 cycles, the subject will escalate to 125 mg for 2 additional cycles. If 1 DLT is observed at 100 mg, an additional 3 subjects will be treated at 100 mg. If 2 or more DLTs are observed at 100 mg, an additional 3 subjects will be treated at 75 mg. If 1 DLT is observed at 75 mg, an additional 3 subjects will be treated at 75 mg. If no DLTs are observed in the first 3 subjects at 100 mg, but 1 DLT is observed at 125 mg, an additional 3 subjects will be treated at 125 mg. If 2 or more DLTs are observed at 125 mg, Cohort 1 will close. If a dose achieves no DLTs in 3 subjects after 2 cycles or 1 DLT in 6 subjects after 2 cycles, that dose will be declared safe for use in the main phase 2 trial.  
If a subject withdraws prior to the completion of the first 2 cycles of therapy without having experienced a DLT, an additional subject will be enrolled at that dose level.
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12.5 secondary safety analysis

The secondary safety analysis relates to the incidence of treatment-emergent adverse events
(TEAEs). TEAEs are those with initial onset or increasing in severity after the first dose of study treatment. TEAEs will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and coded using the Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects who experienced any AE, serious AE (SAE), treatment-related AE, and treatment-related SAE will be summarized according to worst toxicity grades. The summaries will present AEs both on the entire study period and by cycle (Cycle 1 and Cycles beyond 1) in Cohort 1.
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laboratory test abnormalities

The number and percentage of subjects who experienced laboratory test abnormalities will be summarized according to worst toxicity grade observed for each laboratory assay. The analyses will summarize laboratory tests both on the entire study period and by cycle (Cycle 1 and Cycles beyond 1). For laboratory tests without CTCAE grade definitions, results will be categorized as normal, abnormal, or not done.
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12.6 efficacy analysis

Tumor response will be presented in the form of subject data listings that include, but are not limited to:  
The classified integrative subtype (IC2 or IC6) Received (maximum) dose Overall tumor response at each imaging assessment point Best overall response
In addition, disease progression date, death date, date of first response, and last tumor assessment date will be listed, together with progression-free survival. A Kaplan-Meier plot will be created for progression-free survival overall, for IC2-classified tumors separately, and for IC6-classified tumors separately.
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12.7 analysis population

All subjects who received at least one dose of the study drug (infigratinib) will be analyzed for the safety and efficacy outcomes outlined in sections 12.4; 12.5; and 12.6.
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12.8 accrual considerations

There are approximately 600 new breast cancer patients seen annually at the Stanford Cancer Institute, an estimated 50 percent metastatic and 60% HR-positive, HER2-negative. Based on METABRIC, we estimate that approximately 5% of HR-positive, HER2-negative tumors are integrative subtype 2 and 5% are integrative subtype 6.  
2,3 We thus anticipate approximately 20 eligible subjects per year, adequate for the accrual goals. If accrual unexpectedly falls short, additional clinical sites may be added to the study.
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12.9 criteria for future studies

If an MTD for infigratinib in combination with tamoxifen is identified with an acceptable number of DLTs (see Section 12.4), the combination will be deemed acceptable for future studies in this biomarker-selected population of advanced breast cancer. Should this combination prove safe, the study team is planning additional studies to assess efficacy in multiple populations of breast cancer subjects whose tumors harbor FGFR pathway alterations.
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13. references cited

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(2018).  
2. Rueda, O.M. *et al.* Dynamics of breast-cancer relapse reveal late-recurring ER-positive genomic subgroups. *Nature* (2019).  
3. Curtis, C. *et al.* The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. *Nature* 486, 346-52 (2012).  
4. Finn, R.S. *et al.* Efficacy and safety of palbociclib in combination with letrozole as firstline treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18. *Breast* Cancer Res 18, 67 (2016).  
5. Goetz, M.P. *et al.* MONARCH 3: Abemaciclib As Initial Therapy for Advanced Breast Cancer. *J Clin Oncol* 35, 3638-3646 (2017).  
6. Hortobagyi, G.N. *et al.* Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. *N Engl J Med* 375, 1738-1748 (2016).  
7. Cristofanilli, M. *et al.* Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. *Lancet Oncol* 17, 425-439 (2016).  
8. Slamon, D.J. *et al.* Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. *J Clin Oncol* 36, 2465-2472 (2018).  
9. Sledge, G.W., Jr. *et al.* MONARCH 2: Abemaciclib in Combination With Fulvestrant in Women With HR+/HER2- Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. *J Clin Oncol* 35, 2875-2884 (2017).  
10. Kornblum, N. *et al.* Randomized Phase II Trial of Fulvestrant Plus Everolimus or Placebo in Postmenopausal Women With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer Resistant to Aromatase Inhibitor Therapy: Results of PrE0102. *J Clin Oncol* 36, 1556-1563 (2018).  
11. Gradishar, W.J. *et al.* NCCN Guidelines Insights: Breast Cancer, Version 1.2017. J Natl Compr Canc Netw 15, 433-451 (2017).  
12. Itoh, N. The Fgf families in humans, mice, and zebrafish: their evolutional processes and roles in development, metabolism, and disease. *Biol Pharm Bull* 30, 1819-25 (2007).  
13. Nogova, L. *et al.* Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study. *J Clin Oncol* 35, 157-165 (2017).  
14. Pal, S.K. *et al.* Efficacy of BGJ398, a Fibroblast Growth Factor Receptor 1-3 Inhibitor, in Patients with Previously Treated Advanced Urothelial Carcinoma with FGFR3 Alterations. *Cancer Discov* 8, 812-821 (2018).  
15. Javle, M. *et al.* Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced
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Cholangiocarcinoma. *J Clin Oncol* 36, 276-282 (2018).  
16. Turner, N. & Grose, R. Fibroblast growth factor signalling: from development to cancer.  
Nat Rev Cancer 10, 116-29 (2010).  
17. Formisano, L. *et al.* Association of FGFR1 with ERalpha Maintains Ligand-Independent ER Transcription and Mediates Resistance to Estrogen Deprivation in ER(+) Breast Cancer. *Clin Cancer Res* 23, 6138-6150 (2017).  
18. Turner, N. *et al.* FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. *Cancer Res* 70, 2085-94 (2010).  
19. Drago, J.Z. *et al.* FGFR gene amplification and response to endocrine therapy in metastatic hormone receptor positive (HR+) breast cancer. *Journal of Clinical Oncology* 35, 1013-1013 (2017).  
20. Giltnane, J.M. *et al.* Genomic profiling of ER(+) breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance. *Sci Transl Med* 9(2017).  
21. Musolino, A. *et al.* Phase II, randomized, placebo-controlled study of dovitinib in combination with fulvestrant in postmenopausal patients with HR(+), HER2(-) breast cancer that had progressed during or after prior endocrine therapy. *Breast Cancer Res* 19, 18 (2017).  
22. Dillon, P.M. *et al.* A Phase II Study of Dovitinib in Patients with Recurrent or Metastatic Adenoid Cystic Carcinoma. *Clin Cancer Res* 23, 4138-4145 (2017).  
23. Perez-Garcia, J., Munoz-Couselo, E., Soberino, J., Racca, F. & Cortes, J. Targeting FGFR pathway in breast cancer. *Breast* 37, 126-133 (2018).  
24. Milowsky, M.I. *et al.* Phase 2 trial of dovitinib in patients with progressive FGFR3mutated or FGFR3 wild-type advanced urothelial carcinoma. *Eur J Cancer* 50, 3145-52
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25. Loriot Y., N.A., Park S.H., Garcia-Donas J., Huddart R.A., Burgess E.F., Fleming M.T.,
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Zhong B., Stuyckens K., Dosne A-G., Siefker-Radthke A.O. Erdafitinib (ERDA; JNJ42756493), a pan-fibroblast growth factor receptor (FGFR) inhibitor, in patients with metastatic or unresectable urothelial carcinoma and *FGFR* alterations: Phase 2 continuous versus intermittent dosing. *Journal of Clinical Oncology* 36, 411 (2018).  
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27. Formisano, L. *et al.* Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. *Nat Commun* 10, 1373 (2019).  
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30. Yuan, Y., Hess, K.R., Hilsenbeck, S.G. & Gilbert, M.R. Bayesian Optimal Interval Design: A Simple and Well-Performing Design for Phase I Oncology Trials. Clin Cancer Res 22, 4291-301 (2016).
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33. Vlachogiannis, G. *et al.* Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. *Science* 359, 920-926 (2018).  
44. Rugo, H.S. Highlights in breast cancer from the 2017 American Society of Clinical Oncology Annual Meeting. *Clin Adv Hematol Oncol* 15, 607-614 (2017).
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36. Dawson, S.J. *et al.* Analysis of circulating tumor DNA to monitor metastatic breast cancer. *N Engl J Med* 368, 1199-209 (2013).  
37. Murtaza, M. *et al.* Multifocal clonal evolution characterized using circulating tumour DNA
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39. Beechem, J.M. High-Plex Spatially Resolved RNA and Protein Detection Using Digital Spatial Profiling: A Technology Designed for Immuno-oncology Biomarker Discovery and Translational Research. *Methods Mol Biol* **2055**, 563-583 (2020).  
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appendices

APPENDIX A: **List of prohibited medications and substances**  
| Category                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               | Drug Names                                                                                                                                                                                                                                                                                                                                                                                    |
|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Strong inhibitors of CYP3A4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            | clarithromycin, conivaptan, fluconazole, fluvoxamine, indinavir,  itraconazole, ketoconazole, lopinavir, mibefradil, miconazole,  nefazodone, nelfinavir, norfloxacin, posaconazole, ritonavir,  saquinavir, telithromycin, voriconazole grapefruit, grapefruit juice, grapefruit hybrids, pomegranates,  star fruits, pomelos, Seville oranges or products containing  juice of these fruits |
| Strong inducers of CYP3A4                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | avasimibe, carbamazepine, nevirapine, phenobarbital,  phenytoin, pioglitazone, primidone, rifabutin, rifampin, St.  John's wort, troglitazone                                                                                                                                                                                                                                                 |
| Medications which increase  serum phosphorus and/or  calcium                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | calcium, parathyroid hormone, phosphate, vitamin D (including  multivitamins containing vitamin D)                                                                                                                                                                                                                                                                                            |
| Medications with established  potential for QT prolongation or  TdP amiodarone, anagrelide, arsenic trioxide, astemizole (off US  market), azithromycin, bepridil (off US market), chloroquine,  chlorpromazine, cisapride (off US market), citalopram,  clarithromycin, cocaine, disopyramide, dofetilide, domperidone  (not on US market), dronedarone, droperidol, erythromycin,  escitalopram, flecainide, halofantrine, haloperidol, ibutilide,  levofloxacin, levomethadyl (off US market), mesoridazine (off  US market), methadone, moxifloxacin, pentamidine, pimozide,  probucol (off US market), procainamide (oral off US market),  quinidine, sevoflurane, sotalol, sparfloxacin (off US market),  sulpiride (not on US market), terfenadine (off US market),  thioridazine, vandetanib Abbreviations: CYP - cytochrome P; TdP - Torsades de Pointes; US - United States. |                                                                                                                                                                                                                                                                                                                                                                                               |  
| Category                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    | Drug Names   |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|
| CYP3A substrates with narrow  alfentanil, cyclosporine, diergotamine, dihydroergotamine,  therapeutic index ergotamine, fentanyl, sirolimus, tacrolimus, terfenadine,  warfarin sodium or any other coumadin-derivative  anticoagulants, direct thrombin inhibitors (eg, argatroban), and  Factor Xa inhibitors (eg, rivaroxaban) Moderate inhibitors of  amprenavir, aprepitant, atazanavir, cannabinoids, casopitant,  CYP3A4 cimetidine, ciprofloxacin, darunavir, diltiazem, fosamprenavir,  imatinib, metronidazole, Schisandra sphenanthera, sertraline,  suboxone, tofisopam, verapamil, zafirlukast Moderate inducers of CYP3A4 bosentan, cotrimoxazole, efavirenz, etravirine, ethosuximide,  genistein, metyrapone, mexiletine, modafinil, nafcillin,  talviraline, tipranavir Medications which alter the pH  antacids, H2antagonists (eg, ranitidine), proton-pump inhibitors  of the GI tract a,b (eg, omeprazole) Medications that have possible  alfuzosin, amantadine, atazanavir, chloral hydrate, clozapine,  risk of TdP/QT prolongation dolasetron, eribulin, famotidine, felbamate, fingolimod,  foscarnet, fosphenytoin, gatifloxacin, gemifloxacin, granisertron,  iloperidone, indapamide, isradipine, lapatinib, lithium, moexipril,  nicardipine, nilotinib, octreotide, ofloxacin, ondansetron,  oxytocin, paliperidone, pasireotide, quetiapine, ranolazine,  risperidone, roxithromycin, sertindole, sunitinib, tamoxifen,  tizanidine, vardenafil, venlafaxine, ziprasidone Medications that have  conditional risk of TdP/QT  prolongation amitriptyline, amisulpride, ciprofloxacin, clomipramine,  desipramine, diphenhydramine, doxepin, fluoxetine,  galantamine, imipramine, nortriptyline, paroxetine, protriptyline,  sertraline, solifenacin, trazodone, trimethoprim-sulfa,  trimipramine BCRP substrates atorvastatin, irinotecan, methotrexate, rosuvastatin, simvastatin,  sulfasalazine, topotecan Abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome p; F DA, Food and  Drug Administration; GI, gastrointestinal; TdP, Torsades de Pointes a Infigratinib should be dosed at least 2 hours before or 10 hours after dosing with a gastric |              |  
BCRP substrates atorvastatin, irinotecan, methotrexate, rosuvastatin, simvastatin,  
sulfasalazine, topotecan  
Abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome p; F DA, Food and Drug Administration; GI, gastrointestinal; TdP, Torsades de Pointes  
aInfigratinib should be dosed at least 2 hours before or 10 hours after dosing with a gastric  
protection agent.  
bIf possible, proton pump inhibitors should be avoided due to their long pharmacodynamic  
effect and replaced with H2 antagonists or antacids.
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appendix b list of drugs

Lesions that can be accurately measured in at least one dimension. Lesions with longest diameter twice the slice thickness and at least 10 mm or greater when assessed by CT or MRI (slice thickness 5 to 8 mm).  
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper. Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.  
NOTE: The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all other measurable lesions.
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non-measurable disease

Non-measurable disease includes lesions too small to be considered measurable (including nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured with calipers, abdominal masses identified by physical exam that are not measurable by reproducible imaging techniques.  
Bone disease: Bone disease is non-measurable with the exception of soft tissue components that can be evaluated by CT or MRI and meet the definition of measurability at baseline.  
Previous local treatment: A previously irradiated lesion (or lesion subjected to other local treatment) is non-measurable unless it has progressed since completion of treatment.
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normal sites

Cystic lesions: Simple cysts should not be considered as malignant lesions and should not be recorded either as target or non-target disease. Cystic lesions thought to represent cystic metastases can be measurable lesions, if they meet the specific definition above. If non-cystic lesions are also present, these are preferred as target lesions.  
Normal nodes: Nodes with short axis < 10 mm are considered normal and should not be recorded or followed either as measurable or non-measurable disease.
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recording tumor assessments

All sites of disease must be assessed at baseline. Baseline assessments should be done as close as possible prior to study start. For an adequate baseline assessment, all required scans must be done within 28 days prior to treatment and all disease must be documented appropriately. If baseline assessment is inadequate, subsequent statuses generally should be indeterminate.
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target lesions

All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative of all involved organs, should be identified as target lesions at baseline. Target lesions should be selected on the basis of size (longest lesions) and suitability for accurate repeated measurements. Record the longest diameter for each lesion, except in the case of pathological lymph nodes for which the short axis should be recorded. The sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target lesions at baseline will be the basis for comparison to assessments performed on study.  
If two target lesions coalesce, the measurement of the coalesced mass is used. If a large target lesion splits, the sum of the parts is used.  
Measurements for target lesions that become small should continue to be recorded. If a target lesion becomes too small to measure, 0 mm should be recorded if the lesion is considered to have disappeared; otherwise, a default value of 5 mm should be recorded.
NOTE: When nodal lesions decrease to < 10 mm (normal), the actual measurement should still be recorded.
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non-target disease

All non-measurable disease is non-target. All measurable lesions not identified as target lesions are also included as non-target disease. Measurements are not required but rather assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT INCREASED, INCREASED. Multiple non-target lesions in one organ may be recorded as a single item on the case report form (eg, 'multiple enlarged pelvic lymph nodes' or 'multiple liver metastases').
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objective response status at each

Disease sites must be assessed using the same technique as baseline, including consistent administration of contrast and timing of scanning. If a change needs to be made the case must be discussed with the radiologist to determine if substitution is possible. If not, subsequent objective statuses are indeterminate.
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target disease

Complete Response (CR): Complete disappearance of all target lesions with the exception of nodal disease. All target nodes must decrease to normal size (short axis < 10 mm). All target lesions must be assessed.  
Partial Response (PR): Greater than or equal to 30% decrease under baseline of the sum of diameters of all target measurable lesions. The short diameter is used in the sum for target nodes, while the longest diameter is used in the sum for all other target lesions. All target lesions must be assessed.  
Stable: Does not qualify for CR, PR or Progression. All target lesions must be assessed.  
Stable can follow PR only in the rare case that the sum increases by less than 20% from the nadir, but enough that a previously documented 30% decrease no longer holds.  
Objective Progression (PD): 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy), with a minimum absolute increase of 5 mm.  
Indeterminate: Progression has not been documented; and
o One or more target measurable lesions have not been assessed; or 1B  
o Assessment methods used were inconsistent with those used at baseline; or o One or more target lesions cannot be measured accurately (eg, poorly visible unless due to being too small to measure); or o One or more target lesions were excised or irradiated and have not reappeared or increased.
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non-target disease

CR: Disappearance of all non-target lesions and normalization of tumor marker levels. All lymph nodes must be 'normal' in size (< 10 mm short axis).  
Non-CR/Non-PD: Persistence of any non-target lesions and/or tumor marker level above the normal limits.  
PD: Unequivocal progression of pre-existing lesions. Generally, the overall tumor burden must increase sufficiently to merit discontinuation of therapy. In the presence of SD or PR in target disease, progression due to unequivocal increase in non-target disease should be rare.  
Indeterminate: Progression has not been determined and one or more non-target sites were not assessed or assessment methods were inconsistent with those used at baseline.
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new lesions

The appearance of any new unequivocal malignant lesion indicates PD. If a new lesion is equivocal, for example, due to its small size, continued assessment will clarify the etiology. If repeat assessments confirm the lesion, then progression should be recorded on the date of the initial assessment. A lesion identified in an area not previously scanned will be considered a new lesion.
untitled h1
supplemental investigations

If CR determination depends on a residual lesion that decreased in size but did not disappear completely, it is recommended the residual lesion be investigated with biopsy or fine needle aspirate. If no disease is identified, objective status is CR.  
If progression determination depends on a lesion with an increase possibly due to necrosis, the lesion may be investigated with biopsy or fine needle aspirate to clarify status.  
1B  
| Objective Response Status at each Evaluation   |                                          |             |                  |
|------------------------------------------------|------------------------------------------|-------------|------------------|
| Target Lesions                                 | Non-target Lesions                       | New Lesions | Objective status |
| CR                                             | CR                                       | No          | CR               |
| CR                                             | Non-CR/Non-PD                            | No          | PR               |
| CR                                             | Indeterminate or Missing                 | No          | PR               |
| PR                                             | Non-CR/Non-PD, Indeterminate, or Missing | No          | PR               |
| SD                                             | Non-CR/Non-PD, Indeterminate, or Missing | No          | Stable           |
| Indeterminate or                               | Non-PD                                   | No          | Indeterminate    |
| Missing PD                                     | Any                                      | Yes or No   | PD               |
| Any                                            | PD                                       | Yes or No   | PD               |
| Any                                            | Any                                      | Yes         | PD               |