Clinical trial NCT04129151
Conditions: Ewing Sarcoma Ewing's Sarcoma Recurrent
Keywords: Relapsed or refractory Ewing sarcoma Solid Tumor, Childhood Sarcoma Ewing sarcoma
Sponsor: Dana-Farber Cancer Institute
Start date: 2019-12-05; Completion date: 2022-12-15
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is designed to study the combination of two drugs, palbociclib and ganitumab, as a potential treatment for Ewing sarcoma.

The names of the study drugs involved in this study are:

* Palbociclib
* Ganitumab

Detailed description:
This research study involves participants taking a medicine that inhibits proteins in cancer cells called CDK4 and CDK6 (palbociclib) in combination with a medicine that inhibits a protein called IGF-1R (ganitumab). This study is designed to see if these drugs are safe when given together and whether they are effective in treating Ewing sarcoma.

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug or drug combination to learn whether the drug(s) works in treating a specific disease. "Investigational" means that the drug or combination is being studied.

The U.S. Food and Drug Administration (FDA) has not approved ganitumab as a treatment for any disease.

The U.S. Food and Drug Administration (FDA) has not approved palbociclib for this specific disease but it has been approved for another cancer.

This research study is:

* Testing whether palbociclib and ganitumab are safe when given together and effective in treating Ewing sarcoma.
* Testing markers in the blood and in tumor tissue to see if there are certain features of the tumor that may indicate this combination of drugs is effective or not effective

Arms: arm 1: Participants receive up to 12 cycles of therapy (cycle duration=28 days).

* Palbociclib: Oral, 100mg, daily on days 1-21
* Ganitumab: Intravenous, 18mg/kg, days 1, 15

Per protocol, participants were monitored for dose-limiting toxicity over cycle one according to an interim safety analysis. The safety monitoring rule was triggered after 3 patients had enrolled, prompting an amendment according to Contingency Plan A which was a reduction of the palbociclib dose from 125mg (days 1-21).
Interventions: intervention 1: Palbociclib intervention 2: Ganitumab
Intervention descriptions: intervention 1: Oral, per protocol pre determined dosage, once a day for 21 days intervention 2: -Intravenous, per protocol predetermined dosage, twice per cycle

Protocol documents:
Prot_SAP_001.pdf: 
Title: Phase 2 trial of palbociclib and ganitumab in paents 
with relapsed or refractory Ewing sarcoma 
 
NCT Number: 04129151 
 
IRB Approval Date: May 10, 2021 






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0
SCHEMA
This is a prospective, open-label, non-randomized, single arm two-cohort phase 2 clinical trial 
conducted at Dana-Farber/Harvard Cancer Center sites:  Dana-Farber/Boston Children’s Cancer 
and Blood Disorders Center; Dana-Farber/Brigham and Women’s Hospital; and Massachusetts 
General Hospital.  
In November of 2020, new pre-clinical evidence was made available indicating a potential 
vulnerability in SDH-deficient gastrointestinal stromal tumor (GIST) to the combination of 
CDK4/6 inhibition and IGF-1R inhibition.  The study is amended to include one cohort for 
patients with relapsed or refractory Ewing sarcoma (Cohort A), and a second cohort for patients 
with SDH-deficient gastrointestinal stromal tumor (SDH-GIST, Cohort B).  Participants will be 
treated with a CDK4/6 inhibitor (palbociclib) in combination with a monoclonal antibody 
inhibitor of IGF-1R (ganitumab).  Participants in each of the two disease-based cohorts will be 
enrolled in a single-stage design to estimate the radiographic objective response rate as the 
primary endpoint.  Once enrolled, patients will begin therapy in 28-day cycles with palbociclib 
orally once daily on days 1-21 and ganitumab 18 mg/kg IV days 1 and 15 (Figure 1). Cohort A 
will begin therapy with a palbociclib dose of 100 mg daily on days 1-21, while patients in Cohort 
B will begin therapy at a dose of 125 mg daily on days 1-21. 
Disease will be evaluated at baseline, then after cycle 2, 4, 6, 8, 10 and 12 unless otherwise 
clinically indicated.  In the absence of disease progression or unacceptable toxicity, patients may 
receive up to 12 cycles of therapy (approximately 12 months).
As palbociclib and ganitumab have not previously 
been studied in combination, stopping rules will be 
utilized to monitor for unexpected toxicity.  
Screening, Day -28 to -1
Eligible patients with Ewing sarcoma or 
SDH-deficient GIST
Relapsed or refractory disease
Age > 12 years
Disease Evaluation
Treatment
Up to 12 total cycles of therapy
Progressive 
Disease
* Following 
cycles 4, 6, 8, 
10 and 12
Treatment (2 cycles)
> SD
Disease Evaluation*
Progressive 
Disease
Off Protocol 
Therapy
> SD
Treatment:
28-day cycles of treatment
Palbociclib PO daily on Days 1-21
Ganitumab IV on Days 1 and 15
Figure 1: Study schema


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TABLE OF CONTENTS
0
SCHEMA ...............................................................................................................3
1
OBJECTIVES ........................................................................................................6
1.1
Study Design............................................................................................................6
1.2
Primary Objectives...................................................................................................6
1.3
Secondary Objective................................................................................................6
1.4
Correlative Biology Objectives................................................................................7
2
BACKGROUND....................................................................................................7
2.1
Relapsed and Refractory Ewing sarcoma ................................................................7
2.2
Study Agents............................................................................................................7
2.3
Rationale for evaluation of palbociclib and ganitumab in combination................10
2.4
Rationale for evaluation of palbociclib and ganitumab in SDH-Deficient 
GIST.......................................................................................................................11
2.5
Rationale for planned correlative studies...............................................................13
2.6
Overall summary of rationale ................................................................................14
3
PARTICIPANT SELECTION .............................................................................15
3.1
Eligibility Criteria..................................................................................................15
3.2
Exclusion Criteria ..................................................................................................19
3.3
Inclusion of Children and Minorities.....................................................................20
4
REGISTRATION PROCEDURES......................................................................20
4.1
General Guidelines for All Sites............................................................................20
5
TREATMENT PLAN ..........................................................................................20
5.1
Treatment Regimen................................................................................................21
5.2
Pre-Treatment Criteria ...........................................................................................21
5.3
Agent Administration.............................................................................................22
5.4
Dose-Limiting Toxicity (DLT)..............................................................................24
5.5
General Concomitant Medication and Supportive Care Guidelines......................26
5.6
Criteria for Taking a Participant Off Protocol Therapy.........................................27
5.7
Duration of Follow Up...........................................................................................28
5.8
Criteria for Taking a Participant Off Study ...........................................................28
6
DOSING DELAYS/DOSE MODIFICATIONS..................................................28
6.1
Dose Modification for Dose-Limiting Toxicity.....................................................29
6.2
Management of Palbociclib Dose Reductions.......................................................29
6.3
Management of Ganitumab Dose Reductions .......................................................29
6.4
Dose Modifications for Non-Hematologic Toxicity..............................................30
6.5
Dose Modifications for Hematologic Toxicity......................................................34
7
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS...............36
7.1
Introduction to Adverse Event Reporting..............................................................36
7.2
Adverse Event List for Palbociclib........................................................................37


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7.3
Adverse Event List for Ganitumab ........................................................................37
7.4
Adverse Event Characteristics...............................................................................38
7.5
Routine Adverse Event Reporting .........................................................................39
7.6
Expedited Adverse Event Reporting......................................................................40
7.7
Expedited Reporting to the Food and Drug Administration (FDA) ......................41
7.8
Expedited Reporting to Hospital Risk Management .............................................42
7.9
Reporting to Pfizer.................................................................................................42
7.10
Reporting to ImmunityBio, Inc..............................................................................43
8
PHARMACEUTICAL INFORMATION ............................................................44
8.1
Study agents...........................................................................................................44
9
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES...........................48
9.1
Laboratory Correlative Studies..............................................................................48
9.2
Banking for Potential Future Research..................................................................52
9.3
Summary of Blood Volumes for Research Blood Draws......................................53
10
STUDY CALENDAR..........................................................................................54
11
MEASUREMENT OF EFFECT..........................................................................56
11.1
Key Definitions......................................................................................................56
11.2
Antitumor Effect....................................................................................................56
11.3
Response Review...................................................................................................60
12
DATA REPORTING / REGULATORY REQUIREMENTS .............................60
12.1
Data Reporting.......................................................................................................60
12.2
Data Safety Monitoring..........................................................................................61
13
STATISTICAL CONSIDERATIONS.................................................................62
13.1
Study Design/Endpoints ........................................................................................62
13.2
Sample Size, Accrual Rate and Study Duration ....................................................62
13.3
Analysis of Primary Endpoints..............................................................................62
13.4
Interim Toxicity Monitoring Plan..........................................................................64
13.5
Analysis of Secondary Efficacy Endpoints............................................................65
13.6
Analysis of Exploratory Endpoints........................................................................65
14
PUBLICATION PLAN........................................................................................65
15
REFERENCES.....................................................................................................65
APPENDIX A: PERFORMANCE STATUS SCALES/SCORES................................................70
APPENDIX B: DRUG EXCLUSIONS AND INTERACTIONS FOR PALBOCICLIB.............71
APPENDIX C: CORRELATIVE BIOLOGY WORKSHEETS ...................................................73


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1
OBJECTIVES
1.1
Study Design
This is a prospective, open-label, non-randomized, single arm two cohort phase 2 clinical trial.  
Cohorts of patients with relapsed or refractory Ewing sarcoma (Cohort A) or SDH-deficient 
GIST (Cohort B) will be enrolled and treated with a combination of palbociclib and ganitumab. 
The study will be conducted at Dana-Farber/Harvard Cancer Center sites:  Dana-Farber/Boston 
Children’s Cancer and Blood Disorders Center; Dana-Farber/Brigham and Women’s Hospital; 
and Massachusetts General Hospital.
The primary study objective is to evaluate the potential efficacy of palbociclib and ganitumab in 
one cohort of patients with relapsed or refractory Ewing sarcoma or (based on preclinical 
rationale presented in 2020) a second cohort of patients with SDH-deficient GIST, using a 
single-stage design in each cohort to assess radiographic objective response as the endpoint for 
the primary objective.
To be evaluable for the assessment of response or toxicity, a patient on either cohort must 
receive at least one dose of either agent.  Additionally, to be evaluable for assessment of 
response, patients must either have evidence of clinical progression or have had at least one 
follow-up disease evaluation of their RECIST measurable disease after initiation of protocol 
therapy.  
Disease will be evaluated at baseline, after cycles 2, 4, 6, 8, 10 and 12.  In the absence of disease 
progression or unacceptable toxicity, patients may receive up to 12 cycles of therapy 
(approximately 12 months).
As palbociclib and ganitumab have not previously been studied in combination, stopping rules 
will be utilized to monitor for unexpected toxicity.  Given that toxicity profiles of patients with 
Ewing sarcoma and GIST may not overlap, there will be separate stopping rules for Cohort A 
and Cohort B.
1.2
Primary Objectives
1.2.1
To estimate the objective radiographic response rate to the combination of palbociclib 
and ganitumab in a cohort of patients with relapsed or refractory Ewing sarcoma or in a 
separate cohort of patients with SDH-deficient GIST.   
1.2.2
To describe the toxicity of the combination of palbociclib and ganitumab in patients with 
relapsed or refractory Ewing sarcoma, as well as in a separate cohort of patients with 
SDH-deficient GIST.
1.3
Secondary Objective


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1.3.1
To estimate progression-free survival and overall survival in patients with relapsed or 
refractory Ewing sarcoma as well as in the separate cohort of patients with SDH-deficient 
GIST treated with the combination of palbociclib and ganitumab.
1.4
Correlative Biology Objectives
1.4.1
To evaluate serial measurements of circulating tumor DNA burden as a surrogate marker 
of response to protocol therapy.
1.4.2
To evaluate serial measurements of IGF-1 related serum proteins as potential 
pharmacodynamic markers of IGF pathway inhibition.
1.4.3
To explore secondary somatic mutations and tumor protein and RNA markers as potential 
predictive markers of clinical benefit from the combination of palbociclib and ganitumab.  
1.4.4
To bank tumor material, germline DNA, and peripheral blood for potential future 
research for participating subjects who provide additional consent.  
2
BACKGROUND 
2.1
Relapsed and Refractory Ewing sarcoma
Ewing sarcoma
Ewing sarcoma is a rare, aggressive malignancy of bone and soft tissue, most commonly 
affecting adolescents and young adults. Patients with localized Ewing sarcoma have a 70-75% 
overall survival with surgery, and/or radiation for local control, and compressed every two-week 
cycles of vincristine, doxorubicin and cyclophosphamide, alternating with 
ifosfamide/etoposide.1–3  While serial cooperative group studies have gradually improved 
outcomes for patients with localized Ewing sarcoma, survivors carry a significant burden of late 
effects.  Patients with metastatic Ewing sarcoma transiently respond to therapy, but only a small 
minority of patients will have long-term disease control.4–7  Patients with relapsed Ewing 
sarcoma likewise fare poorly, with only few survivors.8–11 
Ewing sarcoma is a classic translocation-associated malignancy, with nearly all cases carrying an 
identifiable EWSR1 or FUS translocation (most commonly EWRS1/FLI1).  The translocation 
leads to an aberrant fusion oncoprotein that is thought to function as a pathogenic transcription 
factor.  Despite our understanding of the fundamental biology of this disease, targeting this 
transcription factor has been elusive and most strategies have focused on targeting downstream 
vulnerabilities.    
 
2.2
Study Agents
2.2.1
Ganitumab: IGF-1R inhibitor














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R1507.40  Total and free serum IGF-1 levels also correlated with outcomes in patients with 
relapsed Ewing sarcoma treated with figitumumab.26  Increases in growth hormone, insulin, and 
IGFBP3 have also been reported in patients with Ewing sarcoma treated with IGF-1R 
monoclonal antibodies, though the impact of these changes on outcomes have not yet been 
reported.24,26  In preclinical studies, upregulation of IGF-2 expression has been described as a 
mechanism of resistance to IGF-1R inhibition in Ewing sarcoma, though not yet evaluated as a 
potential biomarker of resistance in clinical studies.41 In SDH-deficient GIST patients treated 
with the small molecule IGF-1R inhibitor linsitinib, higher levels of IGF-1 and insulin were 
found in circulation while on study compared to baseline.35
The genetic landscape of Ewing sarcoma has recently been described by several groups and 
highlights the relative paucity of mutations in this disease.  In addition to EWSR1/ETS 
translocations, a subset of these tumors harbor STAG2, TP53, and CDKN2A mutations.  
Similarly, SDH-deficient GIST has been described to have a paucity of secondary mutations, 
though this has not been formally examined using modern sequencing approaches. We will use 
next generation sequencing techniques to assess these and other mutations in archival tumor 
material to determine if the presence of these mutations impacts the likelihood of clinical benefit 
to protocol therapy.  We will also have an opportunity to interrogate the ctDNA for these same 
mutations over time in response to protocol therapy.    
2.6
Overall summary of rationale 
Studies of IGF-1R monoclonal antibodies administered as a single agent to patients with relapsed 
Ewing sarcoma provide proof-of-concept that this strategy has activity in this context, though 
objective response rates are low.  Compelling preclinical data demonstrate that combining IGF-
1R inhibition with CDK4/6 inhibition leads to synergistic activity in Ewing sarcoma.  We will 
now test this combination in a phase 2 clinical trial of palbociclib and ganitumab for patients 
with relapsed or refractory Ewing sarcoma.  
Given the favorable toxicity profile of both agents and the dismal outcomes for this population, 
maximizing exposure to this combination is a priority.  Dosing in this trial initially utilized the 
established combination therapy dose for palbociclib of 125 mg PO once daily for 21 days out of 
every 28-day cycle as well as the dose of ganitumab (18 mg/kg IV on days 1 and 15) that has 
been shown to be tolerable in combination with intensive multiagent chemotherapy 
(AEWS1221).  Palbociclib is FDA approved as combination therapy with aromatase inhibitors or 
fulvestrant at a dose of 125 mg.  A drug-drug interaction between this small molecule inhibitor 
and a monoclonal antibody is not anticipated.  Nevertheless, as palbociclib and ganitumab have 
not previously been studied in combination, the protocol includes stopping rules to monitor for 
an unanticipated safety signal.  
Given that two initial patients treated on the Ewing sarcoma cohort (Cohort A) with palbociclib 
125 mg dosing experienced first cycle DLTs, a contingency dosing strategy was enacted on 
1/8/2020 and subsequent patients have started treatment with 100 mg dosing on days 1-21 of a 
28-day cycle.


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In November of 2020, new pre-clinical evidence was made available indicating a potential 
vulnerability in SDH-deficient GIST to the combination of CDK4/6 inhibition and IGF-1R 
inhibition.  Given the lack of effective options for this cohort of patients this study was amended 
to include a parallel single stage cohort (Cohort B) for patients with SDH-deficient GIST. 
Patients in this cohort will enroll to full dose palbociclib (125 mg daily on days 1-21 of a 28-day 
cycle; and ganitumab: 18 mg/kg IV on days 1 and 15).  Unlike patients with Ewing sarcoma, 
patients with SDH-deficient GIST do not receive maximally intensive cytotoxic chemotherapy as 
frontline therapy and thus are not predicted to experience the same degree of hematologic 
toxicity with this combination.  Given the toxicity profile of these agents may differ significantly 
in patients with GIST given the vast differences in upfront therapy, Cohort B will have a toxicity 
monitoring rule that is separate from Cohort A.
3
PARTICIPANT SELECTION
Prior to approaching a potential participant, treating investigators should reserve a treatment slot 
by contacting the Study Coordinator.  Upon reserving a treatment slot, an investigator may begin 
the informed consent process for that participant.  Once informed consent has been obtained, the 
investigator may begin screening studies to confirm eligibility.  Once all eligibility criteria have 
been satisfied, the investigator may enroll the participant according to Section 4.0.
Baseline laboratory tests and ECG must be completed within 14 days prior to the date of 
enrollment.  Laboratory tests used to meet eligibility requirements may be completed within 14 
days prior to date of enrollment, but select tests must be repeated within 5 days prior to dosing 
on Cycle 1, Day 1 if obtained > 5 days prior to Cycle 1, Day 1 as described in Section 5.2.  If 
repeat laboratory studies no longer meet eligibility requirements, the patient must not receive 
protocol therapy.  In this case, required studies may be repeated again within 5 days.  If these 
studies now meet eligibility requirements, the patient may proceed with protocol therapy, 
otherwise the patient will be removed from study and replaced.  
Baseline disease assessments (such as MRIs, CT scans, bone marrow biopsies, and nuclear 
medicine studies) must be performed within 28 days prior to the date of enrollment. 
3.1
Eligibility Criteria 
3.1.1
Age > 12 years at time of enrollment for patients with Ewing sarcoma.
3.1.2
Age  > 12 years at time of enrollment for patients with SDH-deficient GIST. 
3.1.3
Karnofsky performance status ≥ 50% for patients ≥16 years of age and Lansky ≥ 
50% for patients <16 years of age (see Appendix A)
3.1.4
Disease Requirement for Cohort A: Participants with Ewing sarcoma must have:


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3.1.4.1 RECIST measurable disease at study entry, including at least one RECIST 
measurable site that has either not been previously radiated or that has had 
progression after prior radiotherapy;
3.1.4.2
Participants must have relapsed or refractory disease for which standard curative 
or palliative measures do not exist or are no longer effective.  
3.1.4.3 Histologic diagnosis consistent with Ewing sarcoma or PNET; and
3.1.4.4 Molecular evidence of translocation involving EWSR1 or FUS (also known as 
TLS), such as FISH, RT-PCR, or next generation sequencing.  If the translocation 
partner is known it must be of the ETS family (i.e. FLI1 or ERG). 
3.1.5
Disease Requirement for Cohort B: Participants with SDH-deficient GIST must 
have:
3.1.5.1 RECIST measurable disease at study entry, including at least one RECIST 
measurable site; and
3.1.5.2 Histologic diagnosis consistent with GIST; and
3.1.5.3 Evidence of SDH-deficiency by immunohistochemistry, or molecular evidence 
of SDHX mutation. 
3.1.6
Patients must have fully recovered (Common Terminology Criteria for Adverse Events 
[CTCAE] version 5 Grade ≤1) from the acute toxic effects of all prior anti-cancer therapy 
except organ function as noted in Section 3.1.6.  Patients must meet the following 
minimum washout periods prior to enrollment:
3.1.6.1 Myelosuppressive chemotherapy: At least 14 days after the last dose of 
myelosuppressive chemotherapy (42 days for nitrosourea or mitomycin C).
3.1.6.2 Radiotherapy: 
At least 14 days after local palliative XRT (small port); 
At least 90 days must have elapsed after craniospinal XRT or if >50% 
radiation of pelvis; 
At least 6-months must have elapsed following TBI or thoracic radiation 
involving the lungs;
At least 42 days must have elapsed if other substantial bone marrow radiation; 
3.1.6.3 Small molecule biologic therapy: At least 7 days following the last dose of a 
biologic agent.  For agents with known adverse events occurring beyond 7 days, 
this duration must be extended beyond the time in which adverse events are 
known to occur.  If extended duration is required, this should be discussed and 
approved by the study chair.
3.1.6.4 Monoclonal antibody: At least 21 days must have elapsed after the last dose of 
antibody. 


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3.1.6.5 Myeloid growth factors: At least 14 days following the last dose of long-acting 
growth factor (e.g. Neulasta®) or 7 days following short-acting growth factor.
3.1.6.6 Immunotherapy: At least 4 weeks since the completion of immunotherapy (e.g. 
tumor vaccines) aside from monoclonal antibodies with immune effects covered 
under Section 3.1.5.4.  
3.1.6.7 Stem Cell Infusion or Cellular Therapies: The patient must have no evidence of 
graft versus host disease and at least 42 days must have elapsed after transplant, 
stem cell infusion, or cellular therapy. 
3.1.6.8 Major Surgery:  At least 2 weeks from prior major surgical procedure.  Note:  
Biopsy and central line placement/removal are not considered major surgery.  
3.1.6.9 CDK4/6 and IGF-1R inhibitors: The participant must not have received a prior 
CDK4/6 inhibitor.  Prior therapy with IGF-1R inhibitor is allowed if the patient 
did not relapse while on IGF-1R therapy.  Patients must not have received prior 
therapy with a combination of CDK4/6 inhibitor and IGF-1R inhibitor.
3.1.7
Participants must have normal organ function as defined below. 
3.1.7.1
Hematologic Requirements for Subjects without Known Bone Marrow 
Involvement by Disease:
Absolute neutrophil count
>1000 /uL
Hemoglobin
> 8 g/dL (transfusion allowed)
Platelets
      ≥100,000 /uL and transfusion independent, 
defined as not receiving a platelet transfusion 
for at least 7 days prior to CBC documenting 
eligibility.  
3.1.7.2
Hematologic Requirements for Subjects with Bone Marrow Involvement by 
Disease as Demonstrated on Clinically-Indicated Bone Marrow Biopsy:
Absolute neutrophil count
>750 /uL
Hemoglobin
> 8 g/dL (transfusion allowed)
Platelets
≥50,000 /uL and transfusion independent, 
defined as not receiving a platelet transfusion 
for at least 7 days prior to CBC documenting 
eligibility.  
Not known to be refractory to platelet or red cell transfusions.  
3.1.7.3
Hepatic Function:
Total bilirubin
≤ 1.5 x upper limit of normal for age
Patients with Gilbert’s syndrome with a total 
bilirubin < 2 x upper limit of normal for age and 


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a direct bilirubin within normal limits are 
permitted.
ALT (SGPT)
≤ 135 U/L 
For the purpose of this study, the ULN for ALT 
is 45 U/L
AST
≤ 90 U/L 
For the purpose of this study, the ULN for AST 
is 30 U/L
Serum albumin 
> 2 g/dL
3.1.7.4
Renal Function:
A serum creatinine based on age/gender as follows:
Maximum Serum
Creatinine (mg/dL)
Age
Male
Female
12 to < 13 years
1.2
1.2
13 to < 16 years
1.5
1.4
≥ 16 years
1.7
1.4
OR
Creatinine clearance ≥ 70 mL/min/1.73 m2 for participants with creatinine 
levels above institutional normal.
3.1.7.5 Adequate Cardiac Function: QTc < 480 msec on ECG
3.1.7.6 Adequate GI Function: Diarrhea < grade 2 by CTCAE version 5
3.1.7.7 Adequate Metabolic Function: Fasting glucose < 160 mg/dL (or < 8.9 mmol/L) 
without the use of antihyperglycemic agents.  If random glucose < 160 mg/dL 
(or < 8.9 mmol/L), fasting value does not need to be obtained. 
3.1.8
Additional Agent-Specific Requirements
3.1.8.1 Patients must be able to swallow pills.
3.1.7.3 For patients with CNS metastatic disease, any baseline neurologic deficits 
(including seizure) must be stable for at least one week prior to study 
enrollment.  
3.1.9
Ability to understand and/or the willingness of the patient (or parent or legally authorized 
representative, if minor) to provide informed consent, using an institutionally approved 
informed consent procedure.  


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3.2
Exclusion Criteria
3.2.1
Patients must not be receiving any of the following concomitant medications:
3.2.1.1 Pharmacologic doses of systemic corticosteroids unless for CNS metastatic 
disease.  For patients with CNS metastatic disease receiving corticosteroids, 
they should be on a stable or decreasing dose over the 7 days prior to 
registration and meet criteria in Section 3.1.6.7. 
For all patients, receipt of systemic physiologic replacement steroids, topical 
and/or inhaled corticosteroids is acceptable.
3.2.1.2 Patients receiving medications that are strong inhibitors or inducers of CYP3A4 
within 7 days of enrollment (refer to Appendix B, Table 10 for prohibited medications)
3.2.1.3 Patients receiving medications that cause significant QTc prolongation as 
outlined in Table 12 of Appendix B.
3.2.2
Patients who have had tumor molecular testing with sequencing of the RB1 gene and 
were found to have RB1 mutation or loss will be excluded.  
3.2.3
Patients with a history of pneumonitis will be excluded.
3.2.4
Pregnant participants will not be entered on this study given that the effects of palbociclib 
and ganitumab on the developing human fetus are unknown.
3.2.5
Because there is an unknown but potential risk for adverse events in nursing infants 
secondary to treatment of the mother with palbociclib and ganitumab, breastfeeding 
mothers are not eligible.  
3.2.6
Participants of child-bearing or child-fathering potential must agree to use adequate 
contraception (hormonal birth control; intrauterine device; double barrier method; or total 
abstinence) throughout their participation, including up until 30 days after last dose of 
palbociclib or ganitumab, whichever was administered last.
3.2.7
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to palbociclib or ganitumab.
3.2.8
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study requirements.
3.2.9
Participants with a personal history of any of the following: syncope due to an intrinsic 
cardiac etiology (note that syncope due to vasovagal episodes or dehydration/orthostasis 
would NOT exclude a participant), pathologic ventricular arrhythmias (including, but not 


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limited to, ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest.
3.2.10 Patients with known HIV, hepatitis B, and/or hepatitis C (testing not required as part of 
screening).  
3.2.11 Patients with a known history of type 1 or type 2 diabetes mellitus. 
3.2.12 Patients with gastrointestinal disease or disorder that could interfere with absorption of 
palbociclib, such as bowel obstruction or inflammatory bowel disease.  
3.2.13 Patients < 40 kg will be excluded given use of palbociclib at non-weight / non-BSA 
based flat dosing. 
 
3.2.14 Patients with prior invasive malignancies within 5 years are excluded, with the exception 
of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in 
situ of the cervix.
3.3
Inclusion of Children and Minorities
Both male and female children and young adults of all races and ethnic groups are eligible for 
this trial.
4
REGISTRATION PROCEDURES
4.1
General Guidelines for All Sites
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (Policy #: REGIST-101) must be followed.  
Eligible participants will be registered in the Clinical Trials Management System (CTMS) 
OnCore.  Registrations must occur prior to the initiation of protocol therapy.  Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied.
An investigator will confirm eligibility criteria and will complete and sign the protocol-specific 
eligibility checklist.
Following registration, participants may begin protocol therapy and should begin protocol 
therapy within 5 calendar days.  Issues that would cause treatment delays should be discussed 
with the Overall Principal Investigator (PI).  If a participant does not receive protocol therapy 
following registration, the participant’s registration on the study must be canceled.  Registration 
cancellations must be made in OnCore as soon as possible. 
5
TREATMENT PLAN




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If screening laboratory and diagnostic studies for registration were obtained > 5 days prior to 
Cycle 1, Day 1, then the following studies must be repeated within 5 days of Cycle 1, Day 1 
and prior to the Cycle 1, Day 1 palbociclib and ganitumab dose: CBC; creatinine or 
creatinine clearance; bilirubin; ALT; serum albumin; fasting or random glucose (see 
Section 3.1.7.7).    
If any of these repeat laboratory studies do not meet organ function requirements in Section 
3.1.7, then the patient must not receive protocol therapy.  In this case, laboratory studies may be 
repeated again within 5 days.  If these laboratory studies now meet eligibility requirements, the 
patient may proceed with protocol therapy, otherwise the patient will be removed from study.  
5.2.2
Subsequent Cycles 
Prior to the start of each subsequent cycle of therapy, patients without bone marrow involvement 
must meet all of the following criteria:

No clinical or radiographic evidence of disease progression;

Meet hematologic, renal, hepatic, and metabolic organ function requirements listed in 
Section 3.1.7, with the following exception:
o
ANC 
≥ 750/uL
o
Platelets  
≥ 75,000/uL and transfusion independent, defined as not 
receiving a platelet transfusion for at least 5 days prior to CBC

All other adverse events at baseline or < grade 2, whichever is lower.
Prior to the start of each subsequent cycle of therapy, patients who enrolled with bone 
marrow involvement as demonstrated on a clinically indicated bone marrow must meet 
all of the following criteria:

No clinical or radiographic evidence of disease progression;

Meet hematologic, renal, hepatic, and metabolic organ function requirements listed in 
Section 3.1.7, with the following exception:
o
ANC 
≥ 500/uL
o
Platelets  
≥ 50,000/uL and transfusion independent, defined as not 
receiving a platelet transfusion for at least 5 days prior to CBC

All other adverse events at baseline or < grade 2, whichever is lower.
Laboratory studies to meet these requirements may be obtained within 3 days of Day 1 of each 
cycle.  
5.3
Agent Administration
5.3.1
Palbociclib
Palbociclib will be administered at 100 mg daily orally on Days 1-21 of each cycle for patients in 
Cohort A and 125 mg daily orally on Days 1-21 of each cycle for Cohort B.


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Palbociclib will be provided as 125 mg, 100 mg or 75 mg pills.
Palbociclib should be taken as follows: 

Patients should be instructed to take their dose at approximately the same time each day 
(+/- 4-hour window acceptable around each dose).  On days when ganitumab is 
administered, the timing of palbociclib administration can proceed independently of the 
timing of ganitumab administration.    

Each dose of palbociclib should be taken with water (no required minimum volume).  

Pills should be swallowed whole and not chewed, crushed or split.  

Palbociclib may be provided as a tablet or capsule formulation. Instructions differ based 
on formulation. Tablets may be taken with or without food.  Capsules must be taken 
within 1 hour of eating.  

If a patient vomits or misses (not taken within 6 hours of the intended time) a dose of 
palbociclib, the patient should take the next dose as scheduled and not redose.  

Patients should inform the investigational site staff of any missed or delayed doses.  
Each dose of palbociclib will be recorded in a medication diary.  The medication diary will be 
returned to clinic staff at the end of each cycle.  Palbociclib blister packs (tablet formulation) or 
pill bottles (capsule formulation) should be returned to the clinic at the start of each subsequent 
cycle.  The study team will perform pill counts.
In the absence of safety data in pregnant animals or humans, women who are pregnant or could 
be pregnant should use gloves when handling palbociclib.  Caregivers should use caution when 
cleaning up emesis, with the use of gloves recommended.  
5.3.2
Ganitumab
Ganitumab is administered via IV on days 1 and 15 of each cycle. 
Ganitumab will be administered at a dose of 18 mg/kg.
Ganitumab should be administered as follows:

The infusion line should be thoroughly flushed with saline before and after administration 
of ganitumab to avoid mixing with other drug products or IV solutions.

The first dose should be administered over 60 minutes without premedication. If well 
tolerated over 60 minutes, subsequent infusions may be administered over 30 minutes, at 
the investigator’s discretion. Infusion times can be extended to a maximum of 120 
minutes for subjects unable to tolerate the 60-minute infusion.  

Doses over 2100 mg should be infused over 120 minutes. If well tolerated over 120 
minutes, subsequent infusions may be administered over 60 minutes at the investigator’s 
discretion. 

The dose of ganitumab is to be based upon the participant’s weight in kg obtained within 
7 days of the start of each cycle.  There is no adjustment for obesity.  


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See section 8.1.2.5 for ganitumab preparation.
5.3.3
Allowed Local Control Measures
Patients may undergo surgery and/or radiotherapy to sites of disease according to the following 
rules:

Only after confirmed response (meaning two consecutive disease evaluation scans 
showing at least a partial response);

Hold both study drugs at least 1 week prior to surgery and for a minimum of 2 weeks 
following surgery;

Hold both study drugs at least 24 hours prior to radiation, during radiation, and for a 
minimum of 1 week following radiation;

Defer to institutional standard for surgical or radiation approaches;

Thoracic radiation is forbidden while on therapy given potential risk of pneumonitis in 
patients treated with ganitumab.
5.4
Dose-Limiting Toxicity (DLT)
5.4.1
Definition of Dose-Limiting Toxicity
Toxicity will be graded using the CTCAE criteria, version 5.  The CTCAE provides descriptive 
terminology and a grading scale for each adverse event listed. A copy of the CTCAE can be 
downloaded from the CTEP home page (http://ctep.cancer.gov).  Any dose-limiting toxicity 
should be reported immediately via email to the overall Principal Investigator and to the Study 
Coordinator. 
Definition of Dose-Limiting Toxicity
DLT is defined as any of the following events that are possibly, probably or definitely 
attributable to palbociclib or ganitumab.  A DLT may occur in any cycle and will guide dose 
modifications, but only DLTs occurring in the first cycle will be used for implementation of the 
safety monitoring rule (Section 13.4).  
Non-Hematological DLT:

Any Grade 3 or higher non-hematological toxicity attributable to palbociclib or ganitumab 
with the specific exclusion of:
o
Grade 3 nausea and vomiting, anorexia, diarrhea or dehydration resolving to < grade 2 
within 72 hours (note that grade 3 diarrhea requiring hospitalization would constitute 
DLT).
o
Grade 3 AST or ALT liver enzyme elevation that return to < grade 2 within 7 days (except 
as below if bilirubin also elevated).  If grade 3 liver enzyme elevation occurs, palbociclib 
and ganitumab should be held and liver enzymes rechecked within 4 days of initial date of 
grade 3 abnormality to determine if DLT criteria have been met. See also Section 6.4. 
Recall: For the purposes of this study the ULN for ALT is defined as 45 U/L and for AST 
is 30 U/L.


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o
Grade 3 hypophosphatemia, hypokalemia, hypocalcemia or hypomagnesemia responsive 
to oral supplementation within 72 hours.

Grade 2 elevation of AST and/or ALT WITH total bilirubin > 2 x ULN, in the absence of 
cholestasis.

Any Grade 2 non-hematological toxicity that persists for ≥ 7 days and is considered sufficiently 
medically significant or sufficiently intolerable by patients that it requires treatment 
interruption.

Any non-hematologic toxicity that results in delay in start of subsequent cycle by > 14 days.
Hematological DLT: 

Hematological dose limiting toxicity is defined as:
o
Grade 4 thrombocytopenia or grade 4 neutropenia of any duration, in the absence of bone 
marrow disease; or
o
Grade 3 or higher febrile neutropenia with or without documentation of infection; or
o
Grade 3 thrombocytopenia in association with a grade 2 or higher bleeding episode; or
o
Delay in the start of subsequent cycle by > 14 days due to thrombocytopenia or 
neutropenia, in patients without known bone marrow disease.
Patients with bone marrow metastatic disease at study entry will not be evaluable for 
hematologic DLT for the purposes of evaluating the toxicity monitoring rule.  Such patients will 
follow the dose modification criteria in Section 6.2.1 in the setting of defined hematologic DLT.  
Any Grade 5 toxicity that is possibly, probably, or definitely attributable to palbociclib or 
ganitumab will be considered a DLT.
Management and dose modifications associated with the above adverse events are outlined in 
Section 6.
5.4.2
Dose de-escalation rules
If at any time, safety stopping rules are met as outlined in section 13.4, enrollment will be paused 
and one of two contingency dosing strategies for subsequent patients will be considered based 
upon the nature of the observed dose-limiting toxicities.  The choice of contingency dose 
strategy will be made by the study committee in consultation with Pfizer and ImmunityBio.  
Upon initial activation of this study, two of the first three enrolled patients in Cohort A 
experienced cycle 1 DLTs.  This met stopping criteria for our interim monitoring rule and 
Contingency A was enacted on 1/8/2020.  Should the new stopping rule as outlined in section 
13.4 be met, Contingency B or C as outlined below will be considered for Cohort A. Cohort B 
has not yet met any stopping critiera.

Contingency A:  Palbociclib 100 mg daily on days 1-21 and ganitumab 18 mg/kg on days 
1 and 15

Contingency B: Palbociclib 75 mg daily on days 1-21 and ganitumab 18 mg/kg on days 1 
and 15


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
Contingency C: Palbociclib 75 mg daily on days 1-21 and ganitumab 12 mg/kg on days 1 
and 15
If a contingency dosing strategy is implemented, the same monitoring rule will apply (starting 
anew with next enrollment).  If criteria are met again for the toxicity monitoring rule, the 
protocol will be flagged for amendment.  Any toxic death will be cause for review by the DSMB 
and the study committee for consideration of protocol amendment. 
5.5
General Concomitant Medication and Supportive Care Guidelines
5.5.1
Concomitant Medications
5.5.1.1 No other cancer chemotherapy or anticancer therapies are allowed except local 
measures specified in section 5.3.3.   
 
5.5.1.2 Appropriate antibiotics, blood products, anti-emetics, fluids, electrolytes and 
general supportive care are to be used as necessary (see Section 5.5.2).  
5.5.1.3
Patients may not receive corticosteroids EXCEPT under the following 
conditions:

Physiologic replacement for patients with adrenal insufficiency

As needed to manage allergic reactions 

To prevent transfusion reactions  

Inhaled or topical administration

In patients with metastatic CNS disease, use of doses that have been stable 
or tapering since enrollment.
5.5.1.4
Subjects must not receive any of the QT prolonging agents in Appendix B, 
Table 12.  QT prolonging agents in Appendix B, Table 13 are to be used with 
caution.
5.5.1.5
Subjects must not receive strong CYP3A inducers or inhibitors (delineated in 
Appendix B, Table 10) within 7 days of enrollment and while on protocol 
therapy.  Subjects receiving moderate CYP3A inhibitors should be monitored 
(see Appendix B, Table 11).  
Subjects receiving concomitant medications metabolized by CYP3A enzymes 
should be monitored at the discretion of the investigator, particularly if the 
concomitant medication has a narrow therapeutic window and/or is known to 
rely strongly on one of these isoenzymes for its metabolism.  Such medications 
may have an interaction with palbociclib.
Patients must avoid consumption of grapefruit products, and Seville oranges or 
products containing the juice of each while on protocol therapy, due to potential 
CYP3A4 interaction with the study medications. Orange juice is allowed.


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Please refer to the palbociclib and ganitumab Investigator’s Brochures for 
additional drug interaction information.
5.5.2
Supportive Care Guidelines
5.5.2.1
Use of Myeloid Growth Factors
Myeloid growth factors are only to be utilized in the setting of grade 3 or 4 
neutropenia together with documented invasive fungal infection, bacteremia, or 
fever with sepsis physiology.  The overall Principal Investigator should be 
notified in the event of myeloid growth factor use.  Patients who receive 
myeloid growth factor for grade 3 neutropenia will be excluded from 
assessment of dose-limiting neutropenia in that cycle.  If a patient receives 
myeloid growth factor, palbociclib and ganitumab must not be resumed until at 
least 48 hours following the last administered dose of short acting myeloid 
growth factor and until at least 7 days following the last administered dose of 
long-acting myeloid growth factor.  
5.5.2.2
Antiemetics
Palbociclib may be emetogenic, but routine use of prophylactic antiemetics is 
not indicated.  For patients who develop nausea, appropriate non-corticosteroid 
antiemetics should be utilized according to institutional guidelines (aprepitant 
is discouraged; see Appendix B).  
5.6
Criteria for Taking a Participant Off Protocol Therapy
Duration of therapy will depend on individual response, evidence of disease progression, and 
tolerance.  Treatment may continue for up to 12 cycles or until one of the following criteria 
applies:

Disease progression

Intercurrent illness that prevents further administration of treatment

Dose-limiting or other toxicity that meets criteria for removal from protocol therapy (see 
Section 6)

Participant demonstrates an inability or unwillingness to comply with the oral medication 
regimen and/or documentation requirements

Participant decides to withdraw from the protocol therapy

Pregnancy

General or specific changes in the participant's condition render the participant unacceptable 
for further treatment in the judgment of the treating investigator
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 


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documented in the case report form (CRF). Alternative care options will be discussed with the 
participant.
When a participant is removed from protocol therapy and/or is off of the study, the participant’s 
status must be updated in OnCore in accordance with REGIST-OP-1.
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI, 
 
 
5.7
Duration of Follow Up
Participants will return to the study center for adverse event follow-up approximately 30 days 
from last dose of protocol therapy.  This period may be extended until resolution of any ongoing 
adverse events.  Participants removed from protocol therapy for unacceptable adverse event(s) 
will be followed until resolution or stabilization of the adverse event.  For participants unable to 
return to the study center for the planned 30-day follow-up visit, documentation of a clinic 
evaluation at their referring center is acceptable.  
Patients will be followed for survival until 1 year from when the last dose of protocol therapy is 
given to the last enrolled participant.  Return to the study center will not be required as part of 
survival follow-up.
5.8
Criteria for Taking a Participant Off Study
Participants will be removed from study when any of the following criteria apply:

Completion of follow-up per section 5.7;

Found to be ineligible, including participants who have repeat organ function laboratory 
studies obtained within 5 days of Cycle 1, Day 1 that do not meet entry eligibility 
requirements.  Participants who are found to have a diagnosis other than Ewing 
sarcoma/PNET, or SDH-deficient GIST during the course of study therapy may continue on 
protocol therapy only if evidence of clinical benefit and only after discussion with the overall 
Principal Investigator.  Such patients will be replaced for the purposes of evaluating the 
primary aim of the study.;

Lost to follow-up;

Withdrawal of consent for data submission;

Death.
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF).
6
DOSING DELAYS/DOSE MODIFICATIONS
Dose delays and modifications will be made as indicated in the following text and table(s). The 
descriptions and grading scales found in the revised NCI Common Terminology Criteria for 


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Adverse Events (CTCAE) version 5.0 will be utilized for guiding dose delays and dose 
modifications. 
6.1
Dose Modification for Dose-Limiting Toxicity
Patients with protocol-defined DLT (Section 5.4.1) will have palbociclib and ganitumab held.  
Except where noted below for specific target toxicities, palbociclib and ganitumab will be held 
until resolution of toxicity to < Grade 1 (or baseline, whichever is higher grade), and then 
palbociclib and ganitumab will be resumed with dose reduction according to Sections 6.2 
(palbociclib) and 6.3 (ganitumab).  If a patient cannot resume therapy within 21 days of holding 
palbociclib and ganitumab, they will be removed from protocol therapy. 
Patients with recurrent DLT (regardless of category of DLT) despite this dose reduction are 
eligible for up to one additional dose reduction of palbociclib.  Patients with recurrent DLT 
despite two dose reductions of palbociclib will be removed from protocol therapy.  If a second 
dose reduction is required for toxicity related to ganitumab, the patient will be removed from 
protocol therapy. 
Patients who meet criteria for permanent discontinuation of one study agent (e.g., severe allergic 
reaction), will be removed from protocol therapy altogether rather than continuing with 
monotherapy.  
6.2
Management of Palbociclib Dose Reductions
Dose reductions for palbociclib are outlined in Table 1. 
Table 1: Palbociclib dose modifications for adverse reactions
Cohort A
Dose Level
Dose of Palbociclib
Starting dose
100 mg daily
First dose reduction
75 mg daily
Cohort B
Dose Level
Dose of Palbociclib
Starting dose
125 mg daily
First dose reduction
100 mg daily
Second dose reduction
75 mg daily
6.3
Management of Ganitumab Dose Reductions
Dose reductions for ganitumab are outlined in Table 2. 


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Table 2: Ganitumab dose modifications for adverse reactions
Dose Level
Dose of Ganitumab
Starting dose
18 mg/kg on days 1 and 15
First dose reduction
12 mg/kg on days 1 and 15
6.4
Dose Modifications for Non-Hematologic Toxicity
6.4.1
Management of QTc Prolongation
QTc prolongation is a potential risk of palbociclib.  In the setting of QTc prolongation, treat 
reversible causes such as serum electrolyte abnormalities and/or reduce usage of concomitant 
QTc-prolonging medications.  See Table 3 for recommended dose modifications in the setting of 
QTc prolongation.
Table 3: Palbociclib dose modifications for prolonged QTc
Grade 2 QTc 
prolongation
Grade 3 QTc 
prolongation
Grade 4 QTc 
Prolongation
Reversible cause 
identified
Treat reversible 
causes
Initiate more frequent 
ECG monitoring 
according to 
investigator’s best 
medical judgement 
until QTc < 480 msec
Continue at the same 
dose level 
Treat reversible 
causes
Withhold treatment 
until QTc < 501 msec
Resume treatment at 
same dose
Initiate more frequent 
ECG monitoring 
according to 
investigator’s best 
medical judgement 
until QTc < 480 msec
Remove from 
protocol therapy
No reversible cause 
identified
Initiate more frequent 
ECG monitoring 
according to 
investigator’s best 
medical judgement 
until QTc < 480 msec
Continue at the same 
dose level
Withhold treatment 
until QTc < 501 msec
Resume treatment at 
one dose level below 
the current dose 
unless the patient has 
had two dose 
reductions of 
palbociclib in which 
case the patient must 
Remove from 
protocol therapy


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be removed from 
protocol therapy
Initiate more frequent 
ECG monitoring 
according to 
investigator’s best 
medical judgement 
until QTc < 480 msec
6.4.2
Management of Hyperglycemia
For patients who develop hyperglycemia (based on random, non-fasting glucose 
levels), discontinue use of corticosteroids before modifying ganitumab dose. If 
hyperglycemia occurs without use of corticosteroids, ganitumab therapy 
modifications should be as follows:
Hyperglycemia Grade
(per CTCAE, under 
Hyperglycemia)
Action
Grade 1
Continue ganitumab.
Grade 2
Continue ganitumab.
Consider consultation with Pediatric Endocrinologist.
Grade 3 or 
Urine glucose > 0.1 g/dL 
Initiate insulin therapy or oral diabetic agent* as indicated.
Hold ganitumab until resolves to ≤ Grade 2 without 
glycosuria.
Resume ganitumab at same dose IF patient is asymptomatic, 
AND serum glucose is consistently < 250 mg/dL (≤ Grade 2) 
without glycosuria AND resolution to < Grade 2 has occurred 
within 2 weeks of interruption. The patient may continue to 
receive concomitant insulin or an oral diabetic agent for the 
management of hyperglycemia while receiving ganitumab. 
If Grade 3 hyperglycemia recurs despite a stable dose of 
insulin or oral diabetic agent OR if resolution to consistent 
levels < Grade 2 requires more than 2 weeks of interruption, 
subsequent doses should be administered with a reduced dose 
of 12 mg/kg/dose.
Grade 4
Initiate insulin therapy as indicated.
If associated with diabetic ketoacidosis or hyperosmolar 
nonketotic syndrome, discontinue ganitumab permanently. 
Otherwise, use the following instructions.  
Hold ganitumab until resolves to ≤ Grade 2.


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Resume ganitumab with a reduced dose of 12 mg/kg/dose IF 
patient is asymptomatic, AND serum glucose is consistently 
< 250 mg/dL (≤ Grade 2) without glycosuria AND resolution 
to ≤ Grade 2 has occurred within 2 weeks of interruption. The 
patient may continue to receive concomitant insulin or an oral 
diabetic agent for the management of hyperglycemia while 
receiving ganitumab.
If resolution to consistent levels < Grade 2 requires more than 
2 weeks of interruption OR if Grade 4 toxicity recurs after re-
challenge with 12 mg/kg, then discontinue ganitumab 
permanently.  
* Recommended guidelines for use of oral diabetic agents:
Initiation of treatment for hyperglycemia should occur under the guidance of a pediatric 
endocrinologist at the local institution. Metformin may be used per local endocrinologist’s 
recommendations.
Other oral anti-hyperglycemic agent may be used at the discretion of the local treating 
institution. Insulin therapy should be directed by specialists in pediatric diabetes with 
the goal of normal fasting blood sugars < 126 mg/dL and HgbA1C < 8%.
6.4.3
Management of ganitumab-related infusion reactions
For patients who have allergic or acute infusion reactions, therapy modifications based on grade 
should be as follows. Guidelines for emergency management of infusion reactions are 
recommendations and institutional standard practice may be used as an alternative.
Grade
Action
Grade 1
Transient flushing 
or rash, drug 
fever < 38◦C (< 
100.4◦ F)
Slow infusion rate by 50% and monitor patient for worsening of 
condition.  Maximum infusion duration is 120 minutes.  
Grade 2
Rash, flushing, 
urticaria, 
dyspnea, drug 
fever ≥ 38◦ C 
(≥ 100.4◦ F)
Stop infusion; symptom control (diphenhydramine hydrochloride 1 
mg/kg (max 50 mg) IV, acetaminophen 10-15 mg/kg (max 650 mg) 
PO or IV for fever, and oxygen if needed).
Resume infusion at 50% of the prior rate once the reaction has 
decreased to ≤ Grade 1. Monitor patient for worsening condition.  
Maximum infusion duration is 120 minutes.  
For subsequent dose, premedicate with diphenhydramine 
hydrochloride 1 mg/kg (max 50 mg) IV.
If Grade 1-2 infusion reactions reoccur with subsequent dose, add 
dexamethasone 0.2 mg/kg (max 10 mg) IV or equivalent to 
premedications above.
(Only dose interruption/discontinuation, but not dose reduction, is 
required for allergic/infusional reactions.)


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Grade 3
Symptomatic 
bronchospasm 
with or without 
urticaria, allergy-
related edema/ 
angioedema, 
hypotension
Stop infusion immediately.
Administer diphenhydramine hydrochloride 1 mg/kg (max: 50 mg) 
IV, dexamethasone 0.2 mg/kg (max: 10 mg) IV (or equivalent), 
bronchodilators for bronchospasms, and other medications as 
medically indicated. Hospital admission should be considered.
Discontinue ganitumab treatment permanently.
Grade 4
Anaphylaxis
Stop infusion immediately 
Administer diphenhydramine hydrochloride 1 mg/kg 
(max 50 mg) IV, dexamethasone 0.2 mg/kg (max 10 mg) IV (or 
equivalent), and other anaphylaxis medications as indicated. 
Epinephrine or bronchodilators should be administered as indicated. 
Hospital admission for observation may be indicated.
Discontinue ganitumab treatment permanently.


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6.5
Dose Modifications for Hematologic Toxicity
Hematologic toxicity is considered an adverse event with the use of palbociclib and has also 
been reported less commonly with IGF-1R monoclonal antibodies, including ganitumab.  
Palbociclib dose modifications are outlined in Sections 6.5.1.  Ganitumab should be held if a 
patient meets criteria for hematologic DLT per Section 5.4.1.  For a patient’s first hematologic 
DLT, palbociclib will be dose reduced, but ganitumab may be resumed without dose 
modification once the patient meets criteria to resume palbociclib according to Table 8 or 9.  For 
recurrent hematologic DLTs despite one palbociclib dose reduction, ganitumab should be 
resumed at a lower dose according to Table 2 in addition to any additional required dose 
reductions for palbociclib.  
6.5.1
Palbociclib Dose Modifications in the Setting of Hematologic Toxicity
Patients with dose-limiting hematologic toxicity should have their palbociclib dose modified 
according to Table 8 or 9 depending on whether they have bone marrow involvement by disease. 


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Table 8: Palbociclib Dose Modification and Management of Hematologic Toxicities for 
Patients without Bone Marrow Involvement by Disease
CTCAE Grade
Palbociclib Dose Modifications
ANC < LLN to 750/uL, or 
platelet count < LLN to 
75,000/uL
No dose modification is required.
ANC <750 to 500/uL, or 
platelet count <75,000/uL 
to 50,000
Continue current dosing.  
Dose reduction is only required if this definition of 
hematologic DLT is met:
o
Delay in the start of subsequent cycle by > 14 days 
due to thrombocytopenia or neutropenia, in the 
absence of bone marrow disease seen on clinically-
indicated bone marrow biopsy.
Platelet count < 50,000 to 
25,000/uL
Hold palbociclib until platelet count recovers to 75,000/uL.  
Resume at prior dose unless one or both of these definitions 
of hematologic DLT is met:
o
Grade 3 thrombocytopenia in association with a 
grade 2 or higher bleeding episode; or
o
Delay in the start of subsequent cycle by > 14 days 
due to thrombocytopenia, in the absence of bone 
marrow disease seen on clinically-indicated bone 
marrow biopsy.
Grade 4 neutrophil count
Suspend dose until ANC improves to > 750 /uL.  
Once recovered, resume at next lower dose (as long as 
neutropenia not due to progressive bone marrow 
involvement, in which case patient must come off protocol 
therapy).
Grade 4 platelet count
Suspend dose until platelet count improves to > 75,000/uL 
and transfusion independent, defined as not receiving a 
platelet transfusion for at least 5 days prior to CBC.
Once recovered, resume at next lower dose (as long as 
thrombocytopenia not due to progressive bone marrow 
involvement, in which case patient off protocol therapy).
Patient requires 
administration of myeloid 
growth factor
Suspend palbociclib dose for at least 48 hours after the last 
dose of myeloid growth factor and until ANC improves to > 
750 /uL.
If growth factor was given in the setting of grade 4 
neutropenia, resume palbociclib at next lower dose unless 
the dose was already reduced for the toxicity that led to the 
use of the growth factor.


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Table 9: Palbociclib Dose Modification and Management of Hematologic Toxicities for 
Patients Enrolling with Bone Marrow Involvement by Disease
Hematologic criteria
Palbociclib Dose Modifications
ANC < LLN - 500/uL, or 
platelet count < LLN - 
50,000/uL
No dose modification is required.
ANC < 500/uL, or platelet 
count < 50,000/uL during 
Cycle 1
Continue current dosing unless:

Life threatening infection; or

Life threatening bleeding.  
Dose reduction is not required unless delay in the start of 
subsequent cycle by > 14 days due to thrombocytopenia 
or neutropenia, then reduce by one dose level.  
ANC < 500/uL, or platelet 
count < 50,000/uL during 
subsequent cycles 
Suspend dose until ANC improves to > 500 /uL and 
platelet count to > 50,000 /uL and transfusion 
independent, defined as not receiving a
platelet transfusion for at least 5 days prior to CBC.
Dose reduction is not required unless delay in the start of 
subsequent cycle by > 14 days due to thrombocytopenia 
or neutropenia, then reduce by one dose level.  
Patient requires administration 
of a myeloid growth factor
Suspend palbociclib dose for at least 48 hours after the 
last dose of short-acting myeloid growth factor or 7 days 
after long-acting growth factor and until ANC improves 
to > 500 /uL.
Follow guidelines in preceding rows if ANC was < 500 
/uL
LLN – Lower Limit of Normal
7
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS 
7.1
Introduction to Adverse Event Reporting
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Sections 7.2 and 7.3) and the characteristics of an 
observed AE (Section 7.4) will determine whether the event requires expedited reporting in 
addition to routine reporting.


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7.2
Adverse Event List for Palbociclib
The following adverse events have been reported in the phase I monotherapy studies of 
palbociclib in adults (see Investigator Brochure).
Greater than 20% Incidence

Diarrhea

Nausea

Constipation

Fatigue

Neutropenia

Anemia

Anorexia

Infection
10-20% Incidence

Vomiting

Abdominal Pain

Leukopenia

Thrombocytopenia

Pyrexia

Nervous System Disorders

Arthralgia

Peripheral Edema

Pain

Dyspnea

Cough

Back Pain

Rash

Insomnia
Rare but serious side effects reported

Interstitial Lung Disease / pneumonitis
For the purposes of determining expectedness for expedited adverse event reporting, all of the 
above adverse events are to be considered expected.  
7.3
Adverse Event List for Ganitumab
The following adverse events have been reported in the monotherapy studies of ganitumab (see 
Investigator Brochure).
Greater than 20% Incidence

Fatigue


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
Nausea

Anorexia

Thrombocytopenia

Vomiting

Pyrexia

Anemia

Dyspnea
10-20% Incidence

Neutropenia

Diarrhea

Rash

Back Pain

Constipation 

Abdominal Pain

Peripheral Edema

Cough

Infusion-related reaction

Anxiety

Arthralgia

Chest Pain

Chills

Hyperglycemia

Depression

Pain
In the recent Phase 3 trial of ganitumab given combination with intensive multiagent 
chemotherapy (AEWS1221), pneumonitis was reported in 5 patients who had received prior 
thoracic radiation.
7.4
Adverse Event Characteristics
Investigators are to provide the following adverse event characteristics for all adverse events 
experienced from start of protocol therapy until 30 days after last dose of palbociclib or 
ganitumab, which ever came later:

CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 5.0.  A copy of the CTCAE version 5.0 can be downloaded from the CTEP 
web site, https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.

Attribution of the AE:
o
Definite – The AE is clearly related to the study treatment.
o
Probable – The AE is likely related to the study treatment.


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o
Possible – The AE may be related to the study treatment.
o
Unlikely – The AE is doubtfully related to the study treatment.
o
Unrelated – The AE is clearly NOT related to the study treatment.

Seriousness of the AE: An AE is to be classified as “serious” (SAE) if it meets any of the 
following criteria:
Death of Patient
An event that results in the death of a patient.
Life-Threatening
An event that, in the opinion of the investigator, would have resulted 
in immediate fatality if medical intervention had not been taken.  
This does not include an event that would have been fatal if it had 
occurred in a more severe form.
Hospitalization
An event that results in an admission to the hospital for any length 
of time.  This does not include an emergency room visit or admission 
to an outpatient facility.
Prolongation of 
Hospitalization
An event that occurs while the study patient is hospitalized and 
prolongs the patient’s hospital stay.
Congenital 
Anomaly
An anomaly detected at or after birth or any anomaly that result in 
fetal loss.
Persistent or 
Significant 
Disability/ 
Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study patient.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, 
influenza, or accidental trauma (e.g., sprained ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately life-
threatening or result in death or hospitalization, but based on medical 
judgment may jeopardize the patient and may require medical or 
surgical intervention to prevent any of the outcomes listed above 
(i.e., death of patient, life-threatening, hospitalization, prolongation 
of hospitalization, congenital anomaly, or persistent or significant 
disability/incapacity). Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
An AE that meets none of the above criteria is considered “non-serious”.  
Note: Seriousness is independent of attribution or expectedness of the AE.  

Expectedness of the AE:  In addition to term, grade, attribution, and seriousness, adverse 
events that have the potential to qualify for expedited reporting (see Section 7.6) are to be 
designated as “expected” or “unexpected”.  For the purposes of determining expectedness, all 
of the adverse events listed in Section 7.2 and 7.3 are to be considered expected.  
 
7.5
Routine Adverse Event Reporting


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All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs that also meet criteria for expedited reporting (see Section 
7.6) must also be reported in routine study data submissions.
7.6
Expedited Adverse Event Reporting 
7.6.1
Criteria for Expedited Adverse Event Reporting
Investigators must report to the Overall PI in an expedited manner any adverse events (AE) that 
occur after the initial dose of study treatment, during treatment, or within 30 days of the last dose 
of treatment if they meet any of the following criteria and are not listed as adverse events exempt 
from expedited reporting in Section 7.6.2:

Serious adverse events;

Other adverse events (serious or not serious) that meet DFCI Institutional Review Board 
Adverse Event Reporting policy for expedited reporting:
o
Grade 2 or 3 unexpected adverse events that are attributed as at least possibly related to 
palbociclib or ganitumab;
o
All Grade 4 unexpected adverse events, regardless of attribution, unless listed as not 
reportable (see section 7.6.2).
Note: Grade 2 and Grade 3 laboratory abnormalities that are considered by the investigator to be 
clinically insignificant and do not require therapy, or adjustment in prior therapy, do not need to 
be reported to the Overall Principal Investigator or the DFCI IRB.
Regardless of treating institution, these expedited reports will be submitted to the Overall 
Principal Investigator using a DF/HCC AE Reporting form.  
The treating institution must notify the Overall Principal Investigator by phone or email of any 
serious adverse event within 24 hours of learning of the event, with a formal written report 
within 3 business days.  
For non-serious AE’s that nevertheless meet the above DF/HCC definition for expedited 
reporting, the following timelines apply for submission of a DF/HCC AE Reporting form to the 
Overall Principal Investigator.    


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DF/HCC Reportable AEs**
Attribution
Gr. 2 & 3 
AE
Expected
Gr. 2 & 3 AE 
Unexpected
Gr. 4 AE 
Expected
Gr. 4 AE
Unexpected
Gr. 5 AE 
Expected or 
Unexpected
Unrelated
Unlikely
Not required
Not required
 Not required
10 working 
days
24 hours*
Possible
Probable
Definite
 Not required
10 working 
days
 Not required 
10 working 
days
    24 hours*
* For participants enrolled and actively participating in the study or for AEs occurring within 30 
days of the last intervention, the AE should be reported within 24 hours of learning of the event.
**Please follow these reporting timelines only if the event qualifies as non-serious.
 
7.6.2
Protocol-Specific Expedited Adverse Event Reporting Exclusions
Unless the adverse event meets the definition of serious, the following grade 2 adverse events do 
not require expedited reporting to the Overall PI or the DFCI OHRS: nausea; vomiting; fatigue; 
anemia; anorexia; headache; constipation; diarrhea; dry mouth.
Unless the adverse event meets the definition of serious, lymphopenia of any grade does not 
require expedited reporting to the Overall PI or the DFCI OHRS.  
7.7
Expedited Reporting to the Food and Drug Administration (FDA)
The study sponsor and IND holder will be responsible for all communications with the FDA. The 
IND holder will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA.
Specifically, the IND holder will notify the FDA and all participating investigators in a written 
IND safety report of any adverse experience associated with use of the drug that is both 
serious and unexpected.  Each written notification shall be made as soon as possible, and in no 
event later than 15 calendar days after the sponsor’s initial receipt of the information.  Each 
written notification may be submitted on FDA Form 3500A (MedWatch) or in a narrative format 
and must bear prominent identification of its contents, i.e., “IND Safety Report”.  Follow-up 
information to a safety report should be submitted as soon as the relevant information is 
available.




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7.10 Reporting to ImmunityBio, Inc.
The Overall Principal Investigator will report all serious AEs (SAEs), whether related or not 
related to study drug, and any pregnancies to ImmunityBio Drug Safety within 24 hours with 
regards to ImmunityBio drug use. SAEs should be recorded on the Generic Nant Investigator 
Sponsored Study SAE report form.  in.
For the purposes of reporting to ImmunityBio, a serious adverse event is defined as: (1) death; 
(2) in-patient hospitalization or prolonged hospitalization; (3) life-threatening; (4) persistent or 
significant disability or incapacity; (5) congenital abnormality or birth defect; or (6) other serious 
events that may jeopardize the patient and may require medical or surgical intervention to 
prevent one of the other five listed outcomes. 
All fields on the SAE report form should be completed prior to submitting the SAE report to 
NantBio.  But at minimum, the Reporter information, Subject info, Event term (one per SAE 
report form please), Onset date, SAE criteria, Causality (Suspected or Not suspected for each/all 
Study medications being used) and Expectedness (Labeled or Not Labeled) for the Nant Drug 
being used in your study, according to the IB. (Only Expectedness for the Nant Drug being used 
in the study is required for our use)
If an SAE has been reported to any regulatory authority (the SAE meets expedited reporting 
criteria), please provide us a copy of the regulatory submission.  In addition, please ensure the 
following is provided; the authority reported to, date reported and authority confirmation of 
report receipt.
If only limited information is initially available, follow-up reports are required. (Note: Follow-up 
SAE reports should include the same investigator term(s) initially reported.) If an ongoing SAE 
changes in its intensity or relationship to study drug or if new information becomes available, a 
follow-up SAE report should be sent within 24 hours to ImmunityBio using the same procedure 
used for transmitting the initial SAE report. All SAEs should be followed to resolution or 
stabilization. The Overall Principal Investigator will ensure that all SAEs in the clinical database 
are reported to ImmunityBio and any applicable health authority during the conduct of the study. 
This reconciliation will occur at least quarterly and be initiated by the sponsor/investigator. 
The 
Overall 
Principal 
Investigator 
will 
request 
a 
reconciliation 
report 
from: 
 During reconciliation, any events found to not be reported 
previously to ImmunityBio must be sent to:
 
The sponsor will be responsible for submitting all safety correspondence to the FDA.  
ImmunityBio will be provided with a simultaneous copy of all Serious Adverse Event submissions 
filed with the FDA or the local IRB.














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9.1.2
Circulating Tumor DNA (ctDNA) – required
9.1.2.1
Sampling Strategy
Two 10 mL tubes of blood will be drawn into provided EDTA (1 tube) and CellSave 
Preservation Tubes (1tube) for Cohort A  and one 10mL tube of blood will be drawn into a 
CellSave Preservation Tube for Cohort Bat the following time points:  

Cycle 1, Day 1, pre-dose

Cycle 1, Day 15, pre-dose

Cycle 2, Day 1, pre-dose

Cycle 3, Day 1, pre-dose

Cycle 5, Day 1, pre-dose

Cycle 7, Day 1, pre-dose

Cycle 9, Day 1, pre-dose

Cycle 11, Day 1, pre-dose

At time of disease progression or other reason off protocol therapy
All samples must be shipped or delivered same day unless drawn on a Friday, Saturday or 
Sunday, in which case they must be stored at room temperature and shipped same day the 
following Monday. EDTA tubes should only be drawn if they can be delivered to the 
 
lab within two hours.
EDTA and CellSave tubes and the derivatives and data drawn under local banking studies (DFCI 
protocol: 17-104) may be used to supplement the timepoints stated above if any are omitted in 
error. The sample, data or derivatives will be transferred from the banking study after appropriate 
approvals and labeling. 
9.1.2.2
Sample Handling Instructions
Blood should be drawn directly into CellSave Preservation Tubes (1 tube) and EDTA tubes (1 tube).  
Tubes should be completely inverted 8-10 times after sample collection.  EDTA tubes should be 
refrigerated if not immediately delivered to the lab and must be delivered to the 
 Lab 
(address below) within two hours of the blood draw.  For patients treated at Massachusetts 
General Hospital, EDTA tubes do not need to be obtained and instead a single CellSave 
Preservation Tube should be collected at the above time points.  No other on-site processing is 
required.  CellSave samples should be kept at room temperature until shipped.  DO NOT 
REFRIGERATE CellSave tubes.
9.1.2.3
Sample Labeling Instructions
CellSave Preservation Tubes and EDTA tubes should be labeled with the patient’s study ID 
number, the words “Pediatric palbo-ganitumab”, the date of blood draw, and one of the 
following indicators of the sample timing:

Cycle #, Day #

Off protocol therapy
No other identifiers should be included on the label.






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For patients who provide additional consent for banking, remaining tumor material, PBMCs, 
blood, extracted nucleic acids will be stored for up to 5 years after the completion of the trial for 
potential future correlative biology studies and correlation with clinical data.  Future research 
may be performed at the Dana-Farber Cancer Institute or with outside collaborating 
Investigators.  If samples and data are shared with outside collaborators the information will be 
processed in a deidentified manner.   
9.3
Summary of Blood Volumes for Research Blood Draws
Cohort A:
The volume needed for the required correlative biology draws is 45 mL in Cycle 1, 25 mL in 
Cycle 2, 20 mL in Cycle 3, and 5 ml in Cycle 4.  Subsequently, 20 ml of blood will be drawn at 
the start of cycle 5, 7, 9 and 11, and at time of progression or other reason for off protocol 
therapy.  Assuming a 40 kg patient enrolls, 45 mL will represent 1.5% of that patient’s estimated 
blood volume of 3000 mL.
Cohort B:
The volume needed for the required correlative biology draws is 35 mL in Cycle 1, 15 mL in 
Cycle 2, 10 mL in Cycle 3, and 5 ml in Cycle 4.  Subsequently, 10 ml of blood will be drawn at 
the start of cycle 5, 7, 9 and 11, and at time of progression or other reason for off protocol 
therapy.  Assuming a 40 kg patient enrolls, 35 mL will represent 1% of that patient’s estimated 
blood volume of 3000 mL.
If a treating site or investigator has concerns about this volume of blood for a specific patient, 
prioritize the serum separator tube, followed by the CellSave tube then lastly the EDTA tube. 


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10 STUDY CALENDAR
Baseline laboratory tests and ECG must be completed within 14 days prior to the date of 
enrollment.  Laboratory tests used to meet eligibility requirements may be completed within 14 
days prior to date of enrollment, but select tests must be repeated prior to Cycle 1, Day 1 if 
obtained > 5 days prior to Cycle 1, Day 1 as described in section 5.2.  Baseline disease 
assessments, such as MRIs, CT scans and nuclear medicine studies, must be performed within 28 
days prior to the date of enrollment. 
Once enrolled, required observations should be obtained within + 3 days of the protocol-
specified date, unless otherwise noted.  Start of subsequent cycles may be +/- 3 days from day 29 
of the previous cycle.
OBTAIN OTHER STUDIES AS NEEDED FOR GOOD PATIENT CARE.
1.
Laboratory studies obtained in screening do not need to be repeated on Cycle 1, Day 1, UNLESS obtained > 5 days 
prior to Cycle 1 Day 1.  In that event repeat the following: CBC; creatinine or creatinine clearance; bilirubin; ALT; 
albumin; fasting glucose or random glucose.  
2.
End of therapy visit and observations should be performed within 7 days of decision to permanently discontinue 
palbociclib and ganitumab (± 7 days).
3.
All participants will have a follow-up visit approximately 30-days following their last dose of study therapy. days 
or until all toxicity related to the study drug has resolved, whichever is longer.  For participants who are unable to 
return to the study center, observations may be performed at referring center.    
4.
Vital signs include temperature, heart rate, blood pressure, respiratory rate, and oxygen saturation.  
Observation
Screening
Cycle 11
Cycle 2
Subsequent 
Cycles
End of 
Therapy2
Follow-
up3
Physical Exam4
(Includes Ht, Wt, BSA, Vital 
signs4; Performance status5 
only during screening)
X
Weekly
Start of cycle 
and day 15
Start of cycle 
and day 15
X
X3
CBC, Diff, Platelets5
X
Twice 
weekly6
Start of cycle 
and weekly6
Start of cycle 
and day 156
X
X3
Electrolytes, Calcium, 
Magnesium, Phosphorus, 
BUN, Serum Creatinine, 
Glucose5
X
Weekly
Start of cycle 
and day 156
Start of cycle 
and day 156
X
X3
AST, ALT, Alk Phos, Total + 
Direct Bilirubin, Albumin,5
X
Weekly
Start of cycle 
and day 156
Start of cycle 
and day 156
X
X3
Serum or urine pregnancy 
test5,7
X
Start of cycle
Start of cycle
ECG
X
Disease evaluation8,9
X
X9
X9
X9
X10
Blood for pharmacodynamic 
markers and ctDNA 
See Section 
9.1
See Section 
9.1
See Section 
9.1
See 
Section 
9.1
Tissue for biomarker studies 
See 
Section 
9.1
See 
Section 
9.1


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5.
Required for verification of eligibility. Creatinine clearance may be required at screening if creatinine does not 
meet criteria in Section 3.1.6.3.    
6.
More frequent CBCs and chemistries may be needed as part of good patient care, particularly if adverse events 
noted during more frequent lab screenings during Cycles 1 and 2.  
7.
Obtain for females 12 years of age and older or post-pubertal.
8.
Studies obtained as part of disease evaluation will depend upon underlying sites of disease and initial imaging 
modalities.  Studies may include anatomic imaging, nuclear imaging, bone marrow biopsies.  Baseline disease 
status tests must be performed < 28 days prior to study registration and subsequent to any intervening therapy.
9.
Perform disease re-staging during Week 3 or 4 of Cycles 2, 4, 6, 8, 10 and 12.  Confirmatory scans will also be 
obtained 4 weeks following initial documentation of an objective response (partial response or better). 
10. Once a participant is off protocol therapy, they will be followed for survival until one year after the last dose of 
protocol therapy is given to the last enrolled patient.  Participants will undergo disease surveillance at the discretion 
of their local treating physician following completion of study therapy.


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11 MEASUREMENT OF EFFECT
The primary endpoint of the study will be assessed by the below criteria.  See Section 10 for 
required disease staging at study entry, after initiation of protocol therapy and during follow-up.  
Confirmatory scans will also be obtained a minimum of 4 weeks following initial documentation 
of an objective response.
11.1 Key Definitions
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started, or death due to any 
cause. Participants without events reported are censored at the last disease evaluation).
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that progressive disease is 
objectively documented, or death due to any cause. Participants without events reported are 
censored at the last disease evaluation.
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements. 
Progression-Free Survival:  Progression-Free Survival (PFS) is defined as the time from 
registration to the earliest time of progression or death due to any cause. Participants alive 
without disease progression are censored at date of last disease evaluation.
Overall Survival: Overall Survival (OS) is defined as the time from registration to death.  
Participants alive are censored at date of last follow-up.
11.2 Antitumor Effect
Response and progression will be evaluated using Response Evaluation Criteria in Solid Tumors 
(RECIST) guideline (version 1.1).42  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria.
11.2.1 Definitions
Measurable disease:  For lesions other than lymph nodes, measurable lesions are defined as those 
that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 
20 mm by chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters).


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For malignant lymph nodes to be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed.
Non-measurable evaluable disease:  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 
considered non-measurable disease.  Leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pneumonitis, inflammatory breast disease, and cystic lesions are all 
considered non-measurable (except as described in Section 11.3.1.3).  Bone lesions are 
considered non-measurable unless associated with a soft tissue lesion that itself meets criteria for 
measurable disease.  
Important notes:  Tumor lesions that are situated in a previously irradiated area are not 
considered measurable or evaluable unless that site meets criteria for progression after 
completion of radiation.
 
Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) unless biopsy proven 
since they are, by definition, simple cysts.
‘Cystic lesions’ thought to represent cystic metastases, particularly if biopsy proven, can be 
considered as measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same participant, these are preferred for 
selection as target lesions.
11.2.2 Requirements for Disease Assessments
Investigators are to determine the optimal mode of disease assessment at baseline, including 
anatomic imaging studies, nuclear medicine studies, clinical measurements, tumor markers, and 
bone marrow biopsies.  The same method of assessment and the same technique should be used 
to characterize each identified and reported lesion at baseline and during follow-up. Imaging-
based evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a 
digital measurement tool.  All baseline evaluations should be performed as closely as possible to 
the beginning of treatment and never more than 28 days before enrollment.
11.2.3 Response Criteria
11.2.3.1
Evaluation of Target Lesions
Target lesions:  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified 
as target lesions and recorded and measured at baseline.  Target lesions should 


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be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal 
lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters. If lymph nodes are to be included in 
the sum, then only the short axis is added into the sum. The baseline sum 
diameters will be used as reference to further characterize any objective tumor 
regression in the measurable dimension of the disease. 
Complete Response (CR):  Disappearance of all target lesions.  Any 
pathological lymph nodes (whether target or non-target) must have reduction in 
short axis to <10 mm.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters 
of target lesions, taking as reference the smallest sum on study (this includes 
the baseline sum if that is the smallest on study).  In addition to the relative 
increase of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm.  (Note:  the appearance of one or more new lesions is also considered 
progressions).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor 
sufficient increase to qualify for PD, taking as reference the smallest sum 
diameters while on study.
11.2.3.2
Evaluation of Non-Target Lesions
Non-target lesions.  All other lesions (or sites of disease) including any 
measurable lesions over and above the 5 target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow up. 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-
pathological in size (<10 mm short axis).
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response.


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Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits.
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  It must be 
representative of overall disease status change, not a single lesion increase.    
Although a clear progression of “non-target” lesions only is exceptional, the 
opinion of the treating physician should prevail in such circumstances, and the 
progression status should be confirmed at a later time by the review panel (or 
Principal Investigator).
11.2.3.3
Evaluation of New Lesions
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent 
something other than tumor (for example, some ‘new’ bone lesions may be 
simply healing or flare of pre-existing lesions). However, a lesion identified on 
a follow-up scan in an anatomical location that was not scanned at baseline is 
considered new and will indicate PD. If a new lesion is equivocal (because of 
small size etc.), follow-up evaluation will clarify if it truly represents new 
disease and if PD is confirmed, progression should be declared using the date 
of the initial scan on which the lesion was discovered.
11.2.3.4
Need for confirmatory testing
RECIST criteria specify the need for confirmation of response a minimum of 4 
weeks from the disease evaluation that first demonstrated a response.  
Responses will be reported as confirmed or unconfirmed based upon the results 
of this restaging.
11.2.3.5
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the 
treatment until disease progression/recurrence (taking as reference for 
progressive disease the smallest measurements recorded since the treatment 
started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria.


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Overall Response Criteria
Target 
Lesions
Non-Target 
Lesions
New 
Lesions*
Overall 
Response
Best Overall Response when 
Confirmation is Required
CR
CR
No
CR
>4 wks Confirmation
CR
Non-CR/Non-
PD
No
PR
CR
Not evaluated
No
PR
PR
Non-CR/Non-
PD/not 
evaluated
No
PR
>4 wks Confirmation
SD
Non-CR/Non-
PD/not 
evaluated
No
SD
Documented at least once >4 
wks from baseline
PD
Any
Yes or No
PD
Any
PD**
Yes or No
PD
Any
Any
Yes
PD
no prior SD, PR or CR

See RECIST 1.1 manuscript for further details on what is evidence of a new lesion.
**        In exceptional circumstances, unequivocal progression in non-target lesions may be
            accepted as disease progression.
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment.
11.3 Response Review
Patients with confirmed objective response (partial response or better) will have de-identified 
imaging studies submitted to the Study Coordinator for central confirmation of response.  
Imaging studies to be submitted include baseline scans, initial scans documenting response, and 
second set of scans confirming response.  When relevant to the patient’s response assessment, 
de-identified copies of bone marrow pathology reports and tumor marker lab reports will be 
submitted as well.  
12 DATA REPORTING / REGULATORY REQUIREMENTS
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0.
12.1 Data Reporting
12.1.1 Method for Data Submission
All sites will submit data using the electronic data capture system, InForm.


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The DFCI Office of Data Quality (ODQ) will perform quality checks on the data for this study.
12.1.2 Timelines for Data Submission
All investigative sites are expected to submit data in InForm according to the following 
timelines.  
Form
Submission Timeline
Eligibility Checklist
Complete prior to registration
On Study Form
Within 14 days of registration
Toxicity Log
(Baseline Adverse events)
Within 14 days of registration
Baseline Disease Assessment Form
Within 14 days of registration
Reporting Period Forms
Cycle 1:  Within 5 business days of the last day of the 
cycle
Other Cycles:  Within 10 days of the last day of the cycle
Toxicity Log
Cycle 1:  Within 5 business days of the last day of the 
cycle
Other Cycles:  Within 10 days of the last day of the cycle
Response Assessment Form
Within 14 days of the completion of disease evaluation
Off Protocol Therapy Form
Within 14 days of completing treatment 
Follow-up Form
Within 14 days of the protocol defined follow up visit date 
and every 3 months once off therapy until 1 year after the 
last enrolled patient receives their final dose of protocol 
therapy
Off Study Form
Within 14 days of being taken off study for any reason
Outcome Form
Within 14 days of being taken off study for any reason
12.2 Data Safety Monitoring
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 
raises any questions about participant safety will be addressed with the Overall PI and study 
team.
The DSMC will review this protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring within 30 
days of intervention; any response information; audit results; and a summary provided by the 
study team. Other information (e.g. scans, laboratory values) will be provided upon request. 


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13 STATISTICAL CONSIDERATIONS
This is a prospective, open-label, non-randomized, single arm two cohort Phase 2 study to test 
for preliminary evidence of efficacy of the combination of palbociclib and ganitumab.  The study 
will be powered to evaluate the efficacy of this combination separately within two different 
cohorts:
A. Cohort A - relapsed or refractory Ewing sarcoma; and,
B. Cohort B - SDH-deficient GIST. 
The cohort of patients with SDH-deficient GIST was added in an amendment developed in 
December 2020.  The toxicity of this combination will be monitored with early stopping rules 
separately in each cohort.
13.1 Study Design/Endpoints
13.1.1 Study Design
The efficacy of the combination of palbociclib and ganitumab will be assessed separately within 
each cohort, using a one-stage design for Cohort A, and a two-stage design for Cohort B.  The 
primary endpoint is a patient’s objective overall response as defined in Section 11.  A 
“responder” is defined as a patient having a confirmed overall response of ≥ PR. 
13.2 Sample Size, Accrual Rate and Study Duration
A total of 15 response evaluable patients with Ewing sarcoma (Cohort A) and 12 response 
evaluable patients with SDH-deficient GIST (Cohort B) will be required to address the primary 
objective.  Patients who are not eligible and/or evaluable for response will be replaced.  
Therefore, given potentially inevaluable patients a maximum of 33 patients with Ewing sarcoma 
or SDH-deficient GIST are expected to enroll.  
Study Duration:  We anticipate that 1-2 patients with Ewing sarcoma and 1-2 patient per GIST 
per month will be available for enrollment.  Enrollment of the maximum sample size of 33 
patients with Ewing sarcoma and GIST will require approximately 18-24 months.  
13.3 Analysis of Primary Endpoints
13.3.1 Evaluability
To be evaluable for the analysis of the primary endpoint (objective response) patients must have 
received at least one dose of palbociclib or ganitumab. Additionally, patients must either have 
evidence of clinical progression or have had at least one follow-up disease evaluation of their 
RECIST measurable disease after initiation of protocol therapy to be evaluable for response.  
Patients who receive non-protocol anti-cancer therapy during the response evaluation period 
after the patient is first considered as having a partial response, but prior to confirmation of this 
status by repeat tumor imaging and before progressive disease is noted, will be considered 
evaluable.  Should dose de-escalation rules be met as per section 5.4.2 for either cohort, all 


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patients prior to de-escalation and following de-escalation will be analyzed as a single cohort 
within either Cohort A or Cohort B for the primary efficacy endpoint. 
13.3.2 Response endpoint
Each patient will be classified as a responder or non-responder.  Responders are defined as 
evaluable patients with either a complete or partial objective response, according to RECIST 
version 1.1.
Cohort A: Among patients with Ewing sarcoma, the response rate will be reported as the 
proportion of responders, among response evaluable patients.  The null hypothesis that the true 
response rate is 10% will be tested against a one-sided alternative. This design requires 15 
evaluable patients to determine whether the proportion responding is less than or equal to 10% 
(the estimated null response rate with IGF-1R inhibition as monotherapy) or greater than or equal 
to 40%.  If the number of responses is 4 or more, the hypothesis that the true response rate is less 
than or equal to 10% will be rejected with a type 1 error rate of 0.056, and we will conclude that 
the combination therapy is worthy of further study in this cohort.  If the number of responses is 3 
or fewer, then the hypothesis that the response rate is greater than or equal to 40% will be 
rejected with power of 91%.  A two-sided exact 95% confidence interval will be placed on the 
proportion of responders.
Cohort B: Among patients with SDH-deficient GIST, the response rate will be reported as the 
proportion of patients with complete or partial response, among response evaluable patients.  The 
null hypothesis that the true response rate is 4% will be tested against a one-sided alternative of a 
32% response rate. This design will be conducted in two stages. 
In stage 1, 7 evaluable patients will be enrolled. If 0 of 7 evaluable patients are responders, there 
is insufficient evidence of efficacy to continue enrollment to the cohort. If ≥1 patients are 
responders, continue to stage 2. 
In stage 2, 5 additional evaluable patients will be enrolled for a total of 12. If ≥ 2 of 12 evaluable 
patients are responders, there is sufficient evidence for further study of the combination therapy 
in this cohort. If < 2 patients are responders, there is insufficient evidence to support further 
study of the combination therapy in this cohort. 
The two-stage design has the following operating characteristics. If the number of responders is 
≥ 2, the hypothesis that the true response rate is less than or equal to 4% will be rejected with a 
type 1 error rate of 0.07.  If the number of responses is < 2, then the hypothesis that the response 
rate is greater than or equal to 32% will be rejected with power of 90%.  
A two-sided 95% confidence interval will be placed on the proportion of responders.
13.3.3 Toxicity endpoint
All toxicities observed will be summarized in terms of type (organ affected or laboratory 


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determination), severity (by NCI CTCAE), and attribution. Tables will be created to summarize 
theses toxicities by cohort and by cycle.  
13.4 Interim Toxicity Monitoring Plan
The primary endpoint for the interim toxicity monitoring rule of the study will be the occurrence 
of a Cycle 1 DLT that is attributable to palbociclib or ganitumab or the combination, as defined 
in Section 5.4.1.  To be evaluable for the interim toxicity monitoring rule of Cycle 1 DLTs, a 
patient must receive at least one dose of either drug and have been followed for at least 30 days 
following the last dose of protocol therapy or to the start of Cycle 2, whichever occurs first.  
Additionally, any patient with Cycle 1 DLT will be considered evaluable for the interim toxicity 
monitoring rule.   Cohorts A and B will have separate toxicity monitoring rules as the rate of 
DLTs is expected to differ by cohort due to differences in frontline therapy for patients in each 
cohort. 
Toxicity as graded by CTCAE v5.0 will be recorded and monitored throughout all cycles of 
therapy.  The number and proportion of toxicities will be tabulated by type, grade, and 
attribution.  A given toxicity will be counted only once in a given patient, at the highest grade 
observed.
13.4.1 Cohort A toxicity monitoring plan
For Cohort A, the original two-stage toxicity monitoring rule was triggered with 2 DLTs out of 
the first 3 evaluable patients.  A new one-stage design has been developed for the remaining 12 
patients, all of whom will be treated at a lower dose level than the first 3 patients (contingency A, 
see Section 5.4.2).
Enroll up to 12 toxicity evaluable patients.  If at any time 3 or more patients have a first cycle 
DLT, enrollment will be paused, the trial will be reviewed by the study committee and the 
DSMC, and a lower dose level will be considered as outlined in Section 5.4.2.  If fewer than 3 of 
12 patients have a first cycle DLT, the dose level will be considered sufficiently safe for further 
study.  This rule has the following operating characteristics.  The null hypothesis is that the 
proportion of patients with a Cycle 1 DLT is ≥39% versus the alternative that the proportion with 
a Cycle 1 DLT is <9%.  The power is 91.3% and the type 1 error is 9.5%.  
13.4.2 Cohort B toxicity monitoring plan
For Cohort B, we will utilize the following one-stage toxicity monitoring rule:
Enroll up to 12 toxicity evaluable patients.  If at any time 3 or more patients have a first cycle 
DLT, enrollment will be paused, the trial will be reviewed by the study committee and the 
DSMC, and a lower dose level will be considered as outlined in Section 5.4.2.  If fewer than 3 of 
12 patients have a first cycle DLT, the dose level will be considered sufficiently safe for further 
study.  This rule has the following operating characteristics.  The null hypothesis is that the 


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proportion of patients with a Cycle 1 DLT is ≥ 39% versus the alternative that the proportion 
with a Cycle 1 DLT is < 9%.  The power is 91.3% and the type 1 error is 9.5%.   
The number and proportion of toxicities will be tabulated within each cohort, by type, grade, and 
attribution.  A given toxicity will be counted only once in a given patient, at the highest grade 
observed.
13.5 Analysis of Secondary Efficacy Endpoints
Progression-free survival (PFS) will be defined as the time from study enrollment to first episode 
of disease progression or death due to disease, with patients without event censored at last 
follow-up. Overall survival (OS) will be defined as the time from study enrollment to death, with 
surviving patients censored at last follow-up.  PFS and OS will be estimated using Kaplan-Meier 
methods separately for each cohort, with standard errors according to Greenwood.  
13.6 Analysis of Exploratory Endpoints
The pharmacodynamic, ctDNA, CTC and tissue biomarker studies (including but not limited to 
DNA sequencing, RNA-Seq and immunohistochemistry) are considered exploratory.  Within the 
group of patients who begin treatment with palbociclib and ganitumab, the mean, standard 
deviation, and median relative change from baseline will be calculated for each marker.  ctDNA 
positivity will be tested for association with PFS and OS using a log-rank test, and quantified 
with hazard ratios.  Association between continuous measures of modulation of these markers 
versus a) occurrence of any DLT and b) clinical response of partial response or better will be 
tested using a Wilcoxon rank-sum test and presented descriptively using box and whisker plots. 
Secondary somatic mutations will be analyzed from tumor material and tested for association 
with objective response using Fisher’s Exact test.
Graphical presentation of tumor marker data will be key to hypothesis development.  Spaghetti 
plots will be used to display the serial measurements of ctDNA and IGF-1 related serum 
proteins.
14 PUBLICATION PLAN
The results are expected to be made public within 24 months of reaching the end of the study. 
The end of the study is the time point at which the last data items are to be reported.  The initial 
release may be an abstract to be presented at a relevant scientific meeting. A full report of the 
outcomes should be made public no later than three (3) years after the end of the study. 
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40. 
Pappo AS, Patel SR, Crowley J, et al. R1507, a monoclonal antibody to the insulin-like 
growth factor 1 receptor, in patients with recurrent or refractory Ewing sarcoma family of 
tumors: Results of a phase II Sarcoma Alliance for research through Collaboration study. J 


DF/HCC Protocol #:  19-373
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Clin Oncol. 2011;29(34):4541-4547. doi:10.1200/JCO.2010.34.0000
41. 
Garofalo C, Manara MC, Nicoletti G, et al. Efficacy of and resistance to anti-IGF-1R 
therapies in Ewing’s sarcoma is dependent on insulin receptor signaling. Oncogene. 
2011;30(24):2730-2740. doi:10.1038/onc.2010.640
42. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
doi:10.1016/j.ejca.2008.10.026


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APPENDIX A: PERFORMANCE STATUS SCALES/SCORES
Performance Status Criteria 
Karnofsky and Lansky performance scores are intended to be multiples of 10 
ECOG (Zubrod) 
Karnofsky 
Lansky* 
Score 
Description 
Score 
Description 
Score 
Description 
100 
Normal, no complaints, no 
evidence of disease 
100 
Fully active, normal. 
0 
Fully active, able to carry on all 
pre-disease performance 
without restriction. 
90 
Able to carry on normal 
activity, minor signs or 
symptoms of disease. 
90 
Minor restrictions in physically 
strenuous activity. 
80 
Normal activity with effort; 
some signs or symptoms of 
disease. 
80 
Active, but tires more quickly 
1 
Restricted in physically 
strenuous activity but 
ambulatory and able to carry 
out work of a light or sedentary 
nature, e.g., light housework, 
office work. 
70 
Cares for self, unable to carry 
on normal activity or do active 
work. 
70 
Both greater restriction of and less 
time spent in play activity. 
60 
Required occasional assistance, 
but is able to care for most of 
his/her needs. 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
2 
Ambulatory and capable of all 
self-care but unable to carry out 
any work activities. Up and 
about more than 50% of waking 
hours 
50 
Requires considerable 
assistance and frequent 
medical care. 
50 
Gets dressed, but lies around 
much of the day; no active play, 
able to participate in all quiet play 
and activities. 
40 
Disabled, requires special care 
and assistance. 
40 
Mostly in bed; participates in 
quiet activities. 
3 
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours. 
30 
Severely disabled, 
hospitalization indicated. 
Death not imminent. 
30 
In bed; needs assistance even for 
quiet play. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
4 
Completely disabled. Cannot 
carry on any self-care. Totally 
confined to bed or chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
10 
No play; does not get out of bed. 
*The conversion of the Lansky to ECOG scales is intended for NCI reporting purposes only.


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APPENDIX B: DRUG EXCLUSIONS AND INTERACTIONS FOR PALBOCICLIB
Palbociclib is predominantly cleared by oxidative metabolism via CYP3A4.  Clinical drug 
interaction studies with a CYP3A inhibitor and CYP3A inducer significantly altered the PK of 
palbociclib and its circulating major metabolites. Therefore, drugs that are strong and moderate 
inducers of CYP3A and/or strong inhibitors of CYP3A should be avoided or substituted if 
necessary. 
The following medications in Table 10 are prohibited.  For medications known to be strong 
CYP3A inhibitors or inducers not listed use must be discussed with the Principal Investigator. 
Table 10: List of prohibited medications with CYP3A interaction
Strong CYP3A Inhibitors
CYP3A Inducers
clarithromycin
indinavir
itraconazole
ketoconazole
lopinavir/ritonavir
nefazodone
nelfinavir
posaconazole
ritonavir
saquinavir
telaprevir
telithromycin
voriconazole
carbamazepine
efavirenz
nevirapine
phenobarbital
phenytoin
rifabutin
rifampin
rifapentine
St. John’s wort
1. Glucocorticoids are allowed for patients with CNS metastatic disease.  However, they should be on a stable or 
decreasing dose over the 7 days prior to registration and meet criteria in Section 3.1.6.7.  Inhaled and topical 
corticosteroids are allowed.
The following medications outlined in Table 11 are discouraged, but not prohibited.
Table 11: List of medications with CYP3A interactions to be used with caution
Moderate CYP3A Inhibitors
Weak CYP3A Inhibitors
aprepitant
conivaptan
crizotinib
diltiazem
dronedarone
erythromycin
fluconazole
fosamprenavir
grapefruit3
grapefruit juice3
imatinib
mifepristone
nilotinib
verapamil
alprazolam
amiodarone
amlodipine
atorvastatin
bicalutamide
cilostazol
cimetidine
ciprofloxacin
cyclosporine
fluvoxamine
fosaprepitant
isoniazid
nicardipine
propofol
quinidine
1.1.1.1.1.1.1 ranolazine


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Palbociclib is associated with a risk of QTc prolongation.
The following medications in Table 12 are prohibited.  
Table 12: List of prohibited QTc prolonging medications
Drug Name
Drug Class
Amitriptyline, Desipramine, Imipramine
Antidepressants
Chloroquine
Antimalarials
Chlorpromazine, Mesoridazine, Risperidone
Antipsychotics
Itraconazole, Ketoconazole
Antifungals
Tacrolimus, Arsenic trioxide, Domperidone 
Miscellaneous drugs
The following medications outlined in Table 13 are discouraged, but not prohibited.
Table 13: List of medications causing QTc prolongation to be used with caution
Drug Name
Drug Class
Dolasetron, Ondansetron, Tropisetron
Anti-emetics
Doxepin, Maprotiline, Venlafaxine
Antidepressants
Gatifloxacin, Moxifloxacin, Sparfloxacin
Quinolone antibiotics
Halofantrine
Antimalarials
Pentamidine, Droperidol, Methadone, Bepridil
Miscellaneous drugs
Thioridazine, Ziprasidone
Antipsychotics


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APPENDIX C: CORRELATIVE BIOLOGY WORKSHEETS 
Form 1:  IGF-1 PHARMACODYNAMIC WORKSHEET
Patient ID:
Ganitumab Dose: 
Cohort A / Cohort B (circle one)
5 mL of blood into serum separator tube (not 
provided)
Cycle
Day
Sample Time Points
# of 
aliquots 
included 
Date and Time
(use 24-hour clock for times;
e.g. 1622 instead of 4:22)
Example:  12/30/16 @ 1622
1
Pre-dose
5 mL
__ 
aliquots
1
ganitumab dose administered:           
_______ mg
1
Pre-dose
5 mL
__ 
aliquots
2
ganitumab dose administered:           
_______ mg
1
Pre-dose
5 mL
__ 
aliquots
4
ganitumab dose administered:           
_______ mg
Total blood volume for PD samples per cycle:  5 mL
Cycle 1:  
Signature of site staff responsible for sample collection 
Date 
Cycle 2:  
Signature of site staff responsible for sample collection 
Date 
Cycle 4:  
Signature of site staff responsible for sample collection 
Date 
INCLUDE A COPY OF THIS WORKSHEET WITH EACH SAMPLE SHIPMENT AND 
RETAIN A COPY AT THE STUDY SITE.


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Form 2:  ctDNA WORKSHEET DFCI 19-373 – Cycles 1 and 2
Patient ID:
Ganitumab Dose:
Palbociclib Dose: 
Cohort A / Cohort B (circle one)
10 mL in CellSave Preservation Tube (provided) AND 
2x 5mL or 1x 10mL EDTA tube (provided, DFCI Only) 
Cycle
Day
Sample Time Points
Volume
Date and Time
(use 24-hour clock for times;
e.g. 1622 instead of 4:22)
Example:  12/30/16 @ 1622
1
1
Pre-dose
[ ] 10 mL
CellSave
[ ] 10 mL
EDTA 
(Cohort A only)
1
15
Pre-dose
[ ] 10 mL
CellSave
[ ] 10 mL
EDTA
(Cohort A only)
2
1
Pre-dose
[ ] 10 mL
CellSave
[ ] 10 mL
EDTA
(Cohort A only)
Total blood volume for ctDNA samples in this cycle:  ___
Cycle 1 Day 1:  
Signature of site staff responsible for sample collection 
Date 
Cycle 1 Day 15:  
Signature of site staff responsible for sample collection 
Date 
Cycle 2 Day 1:  
Signature of site staff responsible for sample collection 
Date 
INCLUDE A COPY OF THIS WORKSHEET WITH EACH SAMPLE SHIPMENT AND 
RETAIN A COPY AT THE STUDY SITE.


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Form 3:  ctDNA WORKSHEET DFCI 19-373 – Disease Evaluation Timepoint
Patient ID:
Ganitumab Dose:
Palbociclib Dose: 
Cohort A / Cohort B (circle one)
10 mL in CellSave Preservation Tube (provided)
AND 2x 5mL or 1x 10mL EDTA tube (not provided, 
DFCI Only)
Cycle
Day
Sample Time Points
Volume
Date and Time
(use 24-hour clock for times;
e.g. 1622 instead of 4:22)
Example:  12/30/16 @ 1622
_____
____
Disease Evaluation
[ ] 10 mL
CellSave
[ ] 10 mL
EDTA
(Cohort A only)
Total blood volume for ctDNA samples per timepoint:  ____
Signature of site staff responsible for sample collection 
Date 
INCLUDE A COPY OF THIS WORKSHEET WITH EACH SAMPLE SHIPMENT AND 
RETAIN A COPY AT THE STUDY SITE.


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Form 4:  ctDNA WORKSHEET DFCI 19-373 – End of Treatment
Patient ID:
Ganitumab Dose:
Palbociclib Dose: 
Cohort A / Cohort B (circle one)
10 mL in CellSave Preservation Tube (provided)
AND 2 5mL or 1 10mL EDTA tube (not provided, DFCI 
Only)
Cycle
Day
Sample Time Points
Volume
Date and Time
(use 24-hour clock for times;
e.g. 1622 instead of 4:22)
Example:  12/30/16 @ 1622
_____
____
Off protocol therapy
[ ] 10 mL
CellSave
[ ] 10 mL
EDTA
(Cohort A only)
Total blood volume for ctDNA samples per timepoint:  ______
Off Protocol:  
Therapy          Signature of site staff responsible for sample collection 
Date 
INCLUDE A COPY OF THIS WORKSHEET WITH EACH SAMPLE SHIPMENT AND 
RETAIN A COPY AT THE STUDY SITE.


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Form 5:  TISSUE BIOMARKER WORKSHEET
Patient ID:
Ganitumab Dose:
Palbociclib Dose: 
Cohort A / Cohort B (circle one)
Time point
[ ]  Pre-enrollment 
          [ ]  Initial diagnosis
          [ ]  Second look surgery
          [ ]  Biopsy or surgery at time of relapse
[ ]  Post-enrollment
          [ ]  Biopsy or surgery at time of progression
          [ ]  Biopsy or surgery in setting of response
Source of material
[ ]  Primary tumor
[ ]  Metastatic lesion
Date of biopsy/surgery
Number of unstained slides 
submitted
 
Signature of site staff responsible for sample collection 
Date 
INCLUDE A COPY OF THIS WORKSHEET WITH EACH SAMPLE SHIPMENT ALONG 
WITH A REDACTED COPY OF THE PATHOLOGY REPORT.  RETAIN A COPY OF THIS 
WORKSHEET AT THE STUDY SITE.