MATCH Treatment Subprotocol Z1K: Ipatasertib in Patients With Tumors With AKT Mutations
Phase: PHASE2
Conditions: Advanced Lymphoma, Advanced Malignant Solid Neoplasm, Refractory Lymphoma, Refractory Malignant Solid Neoplasm, Refractory Multiple Myeloma
Sponsor: National Cancer Institute (NCI)

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The following revisions to the EAY131-Z1K Informed Consent Document have been made in 
this addendum: 
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Table of Contents
Molecular Analysis for Therapy Choice (MATCH) ...................................................... i
MATCH Treatment Subprotocol Z1K: Ipatasertib in Patients with Tumors with AKT 
Mutations ............................................................................................................ 1 
Table of Contents ...................................................................................................... 2 
Schema ...................................................................................................................... 4 
1. Introduction ........................................................................................................ 5 
1.1 
Ipatasertib ................................................................................................. 5 
1.2 
Supporting Preliminary Data ..................................................................... 7 
1.3 
Exclusion of Breast Cancer ........................................................................ 9 
2. Selection of Patients ......................................................................................... 10 
2.1
Eligibility Criteria .....................................................................................10
3.
Ipatasertib Treatment Plan...............................................................................12
3.1 
Administration Schedule ......................................................................... 12 
3.2 
Adverse Event Reporting Requirements ................................................. 12 
3.3 
Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Ipatasertib (NSC 781451) ........................................................................ 15 
3.4 
Dose Modifications ................................................................................. 17 
3.5 
Supportive Care ....................................................................................... 23 
3.6 
Duration of Agent-specific Treatment .................................................... 24 
3.7 
Duration of Follow-Up ............................................................................. 24 
4. Study Parameters .............................................................................................. 25 
4.1 
Therapeutic Parameters for Ipatasertib Treatment ............................... 25 
5. Drug Formulation and Procurement ................................................................. 28 
5.1 
Ipatasertib ............................................................................................... 29 
6. Translational Studies ......................................................................................... 31 
7. References ........................................................................................................ 31 
Appendix I  Patient Pill Calendar ............................................................................. 33 
Appendix II  Actionable Mutations for Sub-Protocol EAY131- Z1K ......................... 40 
Appendix III  CYP3A4/5 Strong Inducers and Potent Inhibitors .............................. 45 
Appendix IV  PI3K/AKT inhibitors in development .................................................. 46 
Appendix V  PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD ......... 48 
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Schema 
Long-Term Follow-Up
Ipatasertib 400 mg PO once daily 
Until progression or unacceptable 
toxicity
Cycle = 28 days
Accrual Goal: 35
 
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1. 
Introduction 
1.1 
Ipatasertib 
Ipatasertib (GDC-0068) is a selective, ATP-competitive inhibitor of AKT21. In vitro, 
Ipatasertib inhibits all 3 isoforms of AKT (IC50 of AKT1, AKT2 and AKT3 of 5, 18 
and 8nM respectively).1 Screening against a broad panel of 225 kinases 
determined that Ipatasertib is highly selective, acting as a potent inhibitor against 
only three additional kinases (including > 70% inhibition against p70S6K – IC50 is 
860 nM). Thus, Ipatasertib displays a > 100-fold selectivity for AKT1 over the 
next most potentially inhibited non-AKT kinase, i.e. p70S6K. In PC-3 (PTEN 
mutant, prostate), BT474M1 (PIK3CA mutant, HER2+ breast), and IGROV-1 
(PTEN and PIK3CA mutant, ovarian) cell lines, downstream targets of AKT 
including PRAS40, Fox01, Fox03, 4EBP1, and S6 are inhibited in a dose- and 
time-dependent manner.22 In PC-3, BT474M1 and MCF7-neo/HER2 (PIK3CA 
mutant, HER2+ breast) cells, a dose-dependent increase in G0-G1 phase 
population has been identified, as well as an increase in apoptotic and necrotic 
populations in the breast cell lines, as determined by Annexin V/PI staining. 
Sensitivity to Ipatasertib is strongly associated with pAKT levels above the 
median value, as well as with loss of PTEN/PTEN mutation. Cell lines with a 
PIK3CA kinase mutation (i.e. exon 20) also demonstrate increased sensitivity, 
while those with a helical (i.e. exon 9) or other domain mutation do not. 
Genentech/Roche has internal data that confirm the growth factor-independent 
activation of AKT by AKT1 mutations E17K, L52R, D323H, D323Y, Q79K, W80R, 
AKT2 mutation E17K, and AKT3 mutation E17K. All of these mutations sensitize 
cells to Ipatasertib in an IL-3-independent BaF3 cell assay. In addition, 
Ipatasertib demonstrated robust tumor growth inhibition in xenograft models of 
human cancer cell lines with alterations known to lead to AKT activation, such as 
LNCaP (PTEN-null, prostate), PC3 (PTEN-null, prostate), HGC-27 (PTEN-null, 
gastric), HCC1954 (PIK3CA mutant, HER2+ breast), TOV-21G (PTEN-null & 
PIK3CA mutant, ovarian), and 537MEL (PTEN-null, melanoma), as well as PDX 
models with PTEN loss or PIK3CA mutations.2 
There are currently no FDA approved AKT inhibitors for cancer treatment.  
Ipatasertib is currently under investigation in phase I, II, and III clinical trials in 
castration resistant prostate cancer and metastatic breast cancer 
(www.clinicaltrials.gov). In a three-stage study1, 30 patients were enrolled in the 
dose-escalation (stage I) and 22 patients in the two dose expansion cohorts (11 
metastatic breast cancer and 5 patients with metastatic castration-resistant 
prostate cancer; stage II)), or all solid tumors (n=6, stage III). The most common 
cancers were breast cancer (n=16) or colorectal cancer (n=14), with a median of 
6 prior lines of therapy (range, 1-17). Oral Ipatasertib was administered daily for 
21 days followed by 7 days off (21/7 day dosing schedule) every 28 days with 
doses ranging from 25-800 mg. Dose limiting toxicities (DLTs) at 800 mg were 
asthenia and nausea. The maximum tolerated dose for Ipatasertib was 600 mg 
daily on a 21-day on/7-day off schedule which was used for the expansion 
cohorts in stage II and stage III; however, the recommended dose for further 
development is 400 mg daily based upon overall tolerability profile. This dose 
level is being evaluated in continuous daily dosing, as well as 21-day on/7-day off 
schedule in phase III studies, with the schedule depending on the combination 
therapy studied. 
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In 51 treated patients in the single agent study, the most common causally-
related grade 2 or greater adverse events across all dose levels were as follows: 
diarrhea (35%), nausea (27%), asthenia (25%), hyperglycemia (10%), decreased 
appetite 6%, rash (6%), and vomiting (6%). Grade 3 events were diarrhea (n=4), 
asthenia (n=3), hypercholesterolemia (n-1), hyperglycemia (n=1), 
hypophosphatemia (n=1), nausea (n=1), and toxic skin eruption (n=1). No grade 
4 events were observed. Timing to the first onset of diarrhea, nausea, fatigue, 
and rash typically occurred during cycle 1. As proof of mechanism, reduction in 
was demonstrated in platelet-rich plasma. 
In terms of exposure, Ipatasertib  400 mg was associated with pGSK3
reduction  80%, and even at doses < 100 mg greater than 50% inhibition was 
observed. In addition, comparing pretreatment and on-treatment tumor biopsies, 
there was a reduction in pRAS40, pEBP1, pS6, and pmTOR in a dose-
dependent manner, as measured by reverse phase protein array. 
There is clinical evidence of anti-cancer activity with Ipatasertib. Across all dosing 
cohorts, 16 of 47 patients (34%) had stable disease or incomplete response, per 
RECIST criteria, and 6 patients had a progression free survival > 6 months (18% 
in those who received 400 mg or 600 mg). Of the 41 patients with known 
molecular status, stable disease was observed in 6/9 patients with PTEN loss, 
PIK3CA, or AKT mutations in their tumor, as compared to 3/9 who had 
progression. Those with a PIK3CA mutation (n=6) or AKT mutation (n=1) 
remained on study longer with Ipatasertib compared to those without these 
mutations (n=33); median treatment time was 84 vs. 63 days. 
Notably, the one patient with an AKT1 mutation (E17K) had a HER2- negative 
metastatic breast cancer that had progressed on liposomal doxorubicin, 
cyclophosphamide, and most recently capecitabine (on drug for ~ 90 days); while 
on Ipatasertib her CA15-3 declined by > 50% and she remained on study for 235 
days (confidential: Genentech). These data suggest that AKT inhibition with 
Ipatasertib may provide a novel therapeutic approach and serve as the rationale 
for investigating this agent in patients with AKT mutated tumors. In addition to 
AKT1 E17K mutations, Genentech has internal data that confirm the enhanced 
sensitivity of AKT1 E17K, L52R and D323H to Ipatasertib. These mutations in 
AKT isoforms disrupt the PH-Kinase domain interaction resulting in activation of 
the kinase activity and promote AKT-dependent survival in IL-3-deprived Ba/F3 
cells. Additional AKT mutations expected to be sensitive to Ipatasertib include 
AKT1 Q79K, AKT1 W80R, AKT1 D323Y, AKT1 D323G, AKT2 E17K and AKT3 
E17K. If there is additional pre-clinical or clinical data that demonstrates the 
benefit of AKT inhibition with other AKT1 mutations or mutations in the other AKT 
isoforms, further discussion about adding these mutations to the panel will occur. 
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Fig 1: The combination of fulvestrant with AKT inhibition (AZD5363) is better than 
monotherapy in a hormone refractory model (A). Long-term study changes in tumor 
volume after withdrawal of AKT inhibitor (B) or the combination (C). 
At the 2015 AACR-NCI-EORTC International Conference on Molecular Targets 
and Cancer Therapeutics, a heavily pre-treated patient (10 prior lines) with an 
AKT1 E17K and ESR D538G mutant ER+ breast cancer was presented4. She 
had previously progressed on fulvestrant as well as AKT inhibition (AZD5363 
monotherapy). When fulvestrant was added to the AKT inhibitor on day 121 of 
AKT inhibitor treatment, follow-up scans showed shrinkage of her primary breast 
tumor and resolution of liver metastasis. In accordance with these findings, in a 
phase Ib/II clinical trial in patients with metastatic castration resistant prostate 
cancer, there was an improved progression free survival advantage in patients 
who received Ipatasertib 400 mg in combination with abiraterone/prednisone 
compared to abiraterone/prednisone alone (Investigator’s Brochure). These 
results led to an ongoing phase III trial, evaluating the potential benefit of the 
combination. These studies demonstrate that the combination of AKT inhibition 
with hormone therapy may delay or overcome resistance to single-agent 
hormone therapy treatment in breast and prostate cancer.  
1.2 
Supporting Preliminary Data  
The PI3K-AKT pathway is one of the most commonly altered pathways in cancer, 
including mutations, somatic copy number abnormalities, increased expression, 
and aberrant signaling5,6. A number of intrinsic and extrinsic survival signals 
induced by several receptors are thought to be transduced downstream through 
the PI3K/AKT pathway. In addition, hyperactivity of this pathway promotes 
resistance to pro-apoptotic signaling induced by chemotherapy and other anti-
neoplastic therapies. 
Overview of PI3K-AKT pathway: 
The PI3K-AKT pathway can be activated upstream by a wide variety of receptor 
protein tyrosine kinases (RTKs; in particular growth factor receptors), cytokine 
receptors, intracellular tyrosine kinases, G-protein coupled receptors, and 
intracellular small GTPases such as Ras6. In the case of RTKs, activation by 
ligand binding results in the non-covalent association of phosphatidylinositol-3 
kinases (PI3Ks) with phosphotyrosine consensus motifs on the intracellular 
domain of the RTK7. One or two src-homology 2 (SH2) domains on the beta 
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Genome Atlas (TCGA)12. PTEN loss of function mutations, silencing by 
methylation and other epigenetic changes, and large scale chromosomal 
changes leading to loss of PTEN are also amongst the more common 
aberrations seen across many different cancer types, and in particular in
metastatic cancer. Germline mutations in PTEN are responsible for the Cowden 
familial cancer syndrome. Mutations in PTEN and PIK3CA do not appear to be 
mutually exclusive, underscoring the complex functioning of the various 
components of the PI3K-AKT pathway13. 
On the other hand, mutations in AKT genes are rarely found in human cancers to 
date13. Activating mutations have been described in a small percentage of breast 
cancers, head and neck squamous cell carcinomas, endometrial cancer, non-
small cell lung cancer, and renal cancers14. An AKT1 point mutation in the 
pleckstrin homology domain that replaces a glutamic acid with lysine (E17K) at 
residue 17 is the most commonly reported mutation, and is thought to confer 
increased activity by promoting its localization to the plasma membrane14. AKT 
E17K mutation, for example, is seen in 2-3% of breast cancer, and other AKT 
mutations have been seen in this tumor as well (BROAD, SANGER, TCGA). 
AKT1 mutations were seen in luminal A, B and the HER2 subset, but not in basal 
type. Other activating mutations reported in the literature include the E49K 
(AKT1) and G171R substitutions (AKT3), which occur in the pleckstrin homology 
domain and in the kinase domain, respectively. Measurement of p-AKT levels in 
both tumors and cancer cell lines confirms a quantitative increase in activated 
AKT as a consequence of these point mutations, and overall levels of p-AKT 
appear to correlate with sensitivity to AKT inhibition14.
In addition to mutations, there are other means of augmenting AKT activity, 
including AKT gene amplification and AKT rearrangements. However, there is no 
evidence of pre-clinical or clinical benefit of an AKT inhibitor, such as Ipatasertib, 
with AKT amplifications or fusions16-18. To date there is no approved targeted
treatment for patients with AKT mutations; this trial may produce clinical 
validation data that such patients can respond to an AKT inhibitor.
1.3
Exclusion of Breast Cancer
Due to recent findings that an excess of breast cancer patients (n=18/26) have 
been accrued to the trial it is now necessary to limit their accrual to avoid 
overrepresentation of tumors of a particular subtype that would make the ‘tumor 
agnostic’ intent of the subprotocol unachievable. This has been modified under 
‘eligibility criteria.’
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2.
Selection of Patients
Each of the criteria in the checklist that follows must be met, along with the eligibility in 
the MATCH Master Protocol, in order for a patient to be considered eligible for this 
study. Use the checklist to confirm a patient’s eligibility. For each patient, this checklist 
must be photocopied, completed and maintained in the patient’s chart. 
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28. 
ECOG-ACRIN Patient No. ____________________________
Patient’s Initials (L, F, M) _______________________
Physician Signature and Date ___________________
NOTE:
Policy does not allow for the issuance of waivers to any protocol specified 
criteria (http://ctep.cancer.gov/protocolDevelopment/policies deviations.htm). 
Therefore, all eligibility criteria listed in Section 2 must be met, without 
exception. The registration of individuals who do not meet all criteria listed in 
Section 2 can result in the participant being censored from the analysis of the 
study, and the citation of a major protocol violation during an audit.  All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.Execofficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu).
NOTE:
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to registration/randomization by the 
treating physician.
NOTE:
All patients must have signed the relevant treatment consent form
2.1
Eligibility Criteria
2.1.1
Patients must fulfill all eligibility criteria outlined in Section 3.1 of 
MATCH Master Protocol (excluding Section 3.1.6) at the time of 
registration to treatment step (Step 1, 3, 5, 7).
2.1.2
Patients must have an AKT mutation as determined via the MATCH 
Master Protocol and described in Appendix II. See Appendix II for 
information on the AKT mutation and corresponding Levels of 
Evidence.
2.1.3
Patients with breast cancer are excluded.
2.1.4
Patients with castration-resistant prostate cancer should maintain 
castrate levels of testosterone (i.e., with GnRH agonists or through 
surgical castration). Patients are allowed to continue abiraterone 
acetate / prednisone with Ipatasertib if the patient just progressed on 
abirterone acetate / prednisone. 
2.1.5
Patients must not have known hypersensitivity to Ipatasertib or 
compounds of similar chemical or biologic composition.
2.1.6
Patients with known KRAS, NRAS, HRAS, or BRAF mutations are not 
eligible for this protocol, as these mutations may lead to limited 
response due to resistance. 
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2.1.7
Patients with diabetes or risk for hyperglycemia are eligible. Patients 
with diabetes mellitus should be on a stable dose of oral 
hypoglycemic agents for 
4 weeks and appropriate diet. Patients with 
diabetes mellitus may enter the study unless any of the following 
exclusion criteria are fulfilled:
Baseline fasting glucose value of >8.9 mmol/L or 160 mg/dL 
(fasting is defined as no calorific intake for at least 8 hours)
Patients not on a stable dose of oral hypoglycemic medication for 
weeks and appropriate diet
Insulin required for routine diabetic management and control
More than two oral hypoglycemic medications required for routine 
diabetic management and control
Hemoglobin A1C 
7.5%
2.1.8
Prior PI3K and mTOR inhibitors are allowed, including in the 
metastatic setting. Prior AKT inhibitors are excluded (See Appendix 
IV). 
2.1.9
Patients with a history of inflammatory bowel diseases (Crohn’s 
disease and ulcerative colitis) or active diverticulitis are not eligible.
2.1.10
Patients may not have received strong inhibitors or potent inducers or 
substrates of CYP3A4/5 within 2 weeks before the first dose of study 
treatment (3 weeks for St John’s Wort). See Section 5.1.8 and 
Appendix III. 
2.1.11
In addition to the patient contraception requirements outlined in 
EAY131 MATCH Master Protocol, male patients must also refrain 
from donating sperm for the duration of study participation, and for 4 
months after completion of study.
Physician Signature
Date
OPTIONAL:
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation.
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3.
Ipatasertib Treatment Plan
3.1 
Administration Schedule
Patients will be instructed to take Ipatasertib 400 mg orally once daily 
continuously for each 28 day cycle, until tumor progression or unless patient 
experiences unacceptable toxicities. Cycles are defined in 28-day periods to 
facilitate scheduling of visits and assessments.  
NOTE:  
Ipatasertib can be taken with or without food. 
If a dose is missed or omitted (not taken within 8 hours after the scheduled 
dosing time), the patient should resume dosing with the next scheduled dose the 
following day. Missed, omitted, or vomited doses will not be made up. In the 
event that a patient vomits later than 30 minutes after Ipatasertib dosing, the 
patient must not retake new capsule(s)/tablet(s), but continue to take the next 
day. If a patient needs to take the dose earlier for whatever reason, the patient 
can take the dose up to 8 hours earlier than the scheduled dose time. The patient 
should make every reasonable effort to take the Ipatasertib capsule(s) / tablets(s) 
on time.
Hormone Therapy (Breast Cancer and/or Prostate Cancer)
If the patient has HR positive/HER2 negative unresectable breast cancer, (s)he is 
allowed to continue fulvestrant or an aromatase inhibitor (anastrazole, letrozole, 
exemestane) with Ipatasertib if (s)he most recently progressed on this anti-
estrogen therapy. For instance, if the last treatment was fulvestrant, the patient is 
allowed to continue the fulvestrant in combination with Ipatasertib. If the patient 
previously was receiving GnRH agonist (such as leuprolide or goserelin), this 
should continue as previously administered.
SERMs, such as tamoxifen or toremifene, are not allowed.
If the patient has metastatic castration resistant prostate cancer, he is allowed to 
continue abiraterone if he just progressed on this agent. GnRH agonists (such as 
leuprolide or goserelin) are allowed. Prednisone/prednisolone is allowed along 
with this combination – up to 10 mg po daily (5 mg po bid is allowed). 
The patient should continue on the same dose and schedule of the prior 
hormone therapy as was previously taken. Hormone therapy administration is per 
FDA-approved package labeling.
Diarrhea Prophylaxis
In this study all patients should receive loperamide (2 mg oral twice a day or 4 
mg once a day) as prophylaxis for diarrhea in the first cycle if allowed by local 
guidance. Investigators are encouraged to continue this dosing for the remainder 
of the study, and the prophylaxis dose may be adjusted as necessary, using their 
discretion based on clinical judgment and per local guidance.
3.2
Adverse Event Reporting Requirements
The Adverse Event Reporting Requirements for all EAY131 subprotocols are 
outlined in the MATCH MASTER protocol. Please refer to those guidelines when 
determining if an event qualifies as a Serious Adverse Event (SAE) and requires 
expedited reporting via CTEP’s Adverse Event Reporting System (CTEP-AERS). 
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In addition, the following section outlines agent specific requirements and must 
be followed to ensure all reporting requirements are met. 
3.2.1
Additional instructions, requirements and exceptions for protocol 
EAY131 – Subprotocol Z1K 
Additional Instructions 
For instructions on how to specifically report events that result in 
persistent or significant disability/incapacity, congenital anomaly, 
or birth defect events via CTEP-AERS, please contact the AEMD 
Help Desk at aemd@tech-res.com or 301-897-7497. This will 
need to be discussed on a case-by-case basis. 
 
EAY131 – Subprotocol Z1K specific expedited reporting 
requirements: 
 
Pregnancies: Pregnancies and suspected pregnancies 
(including a positive or inconclusive pregnancy test, regardless 
of age or disease state) occurring while the female patient is on 
Ipatasertib, or within 28 days of the female patient’s last dose 
of Ipatasertib, are considered immediately reportable events. 
The pregnancy, suspected pregnancy, or positive/ inconclusive 
pregnancy test must be reported via CTEP-AERS within 24 
hours of the Investigator’s knowledge. Please refer to Appendix 
VIII in MATCH Master Protocol for detailed instructions on how 
to report the occurrence of a pregnancy as well as the outcome 
of all pregnancies. 
 
EAY131 – Subprotocol Z1K specific expedited reporting 
exceptions: 
For Subprotocol Z1K, the adverse events listed below do not 
require expedited reporting via CTEP-AERS: 
1. If an AE meets the reporting requirements of the protocol, and 
it is listed on the SPEER, it should ONLY be reported via 
CTEP-AERS if the grade being reported exceeds the grade 
listed in the parentheses next to the event.  
3.2.2 
Second Primary Cancer Reporting Requirements 
All cases of second primary cancers, including acute myeloid 
leukemia (AML) and myelodysplastic syndrome (MDS), that occur 
following treatment on NCI-sponsored trials must be reported to 
ECOG-ACRIN using Medidata Rave 
 
A second malignancy is a cancer that is UNRELATED to any 
prior anti-cancer treatment (including the treatment on this 
protocol).  Second malignancies require ONLY routine reporting 
as follows: 
1. Complete a Second Primary Form in Medidata Rave within 14 
days. 
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2. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave confirming the diagnosis. 
3. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave. 
 
A secondary malignancy is a cancer CAUSED BY any prior anti-
cancer treatment (including the treatment on this protocol). 
Secondary malignancies require both routine and expedited 
reporting as follows: 
1. 
Complete a Second Primary Form in Medidata Rave within 14 
days 
2. 
Report the diagnosis via CTEP-AERS at http://ctep.cancer.gov  
Report under a.) leukemia secondary to oncology 
chemotherapy, b.) myelodysplastic syndrome, or c.) 
treatment related secondary malignancy 
3. Upload a copy of the pathology report to ECOG-ACRIN via 
Medidata Rave and submit a copy to NCI/CTEP confirming the 
diagnosis. 
4. If the patient has been diagnosed with AML/MDS, upload a 
copy of the cytogenetics report (if available) to ECOG-ACRIN 
via Medidata Rave and submit a copy to NCI/CTEP. 
NOTE: 
The Second Primary Form and the CTEP-AERS report 
should not be used to report recurrence or development of 
metastatic disease. 
NOTE: 
If a patient has been enrolled in more than one NCI-
sponsored study, the Second Primary Form must be 
submitted for the most recent trial. ECOG-ACRIN must be 
provided with a copy of the form and the associated 
pathology report and cytogenetics report (if available) even 
if ECOG-ACRIN was not the patient's most recent trial. 
NOTE: 
Once data regarding survival and remission status are no 
longer required by the protocol, no follow-up data should 
be submitted via CTEP-AERS or by the Second Primary 
Form. 
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Based on the potential for phototoxicity, advise patients receiving Ipatasertib to 
avoid excessive sun exposure and to use adequate sunscreen protection if sun 
exposure is anticipated. Patients should avoid using sunbeds/tanning booths. 
3.6 
Duration of Agent-specific Treatment 
In the absence of treatment delays due to adverse event(s), treatment may 
continue until one of the following criteria applies: 
 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
MATCH Forms Packet. 
 
Patient withdraws consent. 
 
Patient experiences unacceptable toxicity. 
 
Non-protocol therapies are administered. 
 
Disease progression 
3.7 
Duration of Follow-Up  
Refer to the MATCH Master Protocol for specifics on the duration of follow-up. 
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7. 
If the patient has castration resistant prostate cancer, he is allowed to continue the abiraterone that he just progressed on. For guidance, it is 
recommended to follow the prescribing information for abiraterone. 
8. 
If the patient is given Fulvestrant and/or a GnRH agonist, these should be given on D1 of the cycle (+/- 7 days). 
9. 
All patients should receive loperamide (2 mg oral twice a day or 4 mg once a day) as prophylaxis for diarrhea in the first cycle if allowed by local 
guidance. Investigators are encouraged to continue this dosing for the remainder of the study, and the prophylaxis dose may be adjusted as 
necessary, using their discretion based on clinical judgment and per local guidance. 
 
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5. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees.
Availability 
NO STARTER SUPPLIES MAY BE ORDERED. Subjects must be enrolled and assigned 
to the treatment subprotocol prior to submitting the clinical drug request to PMB. 
Drug Ordering: NCI supplied agents may be requested by eligible participating 
Investigators (or their authorized designee) at each participating institution. 
Pharmaceutical Management Branch (PMB) policy requires that drug be shipped directly 
to the institution where the patient is to be treated. PMB does not permit the transfer of 
agents between institutions (unless prior approval from PMB is obtained – see general 
information). The CTEP-assigned protocol number must be used for ordering all CTEP-
supplied investigational agents. The eligible participating investigators at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), NCI Biosketch, Agent 
Shipment Form, and Financial Disclosure Form (FDF). If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study 
should be ordered under the name of one lead investigator at that institution. 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application (https://ctepcore.nci.nih.gov/OAOP/). Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account 
(https://ctepcore.nci.nih.gov/iam/) and the maintenance of an “active” account status, a 
“current” password, and an active person registration status. 
NCI Supplied Agent(s) – General Information 
Questions about drug orders, transfers, returns, or accountability should be 
addressed to the PMB by calling 240-276-6575 Monday through Friday between 
8:30 AM and 4:30 PM Eastern Time or email PMBAfterHours@mail.nih.gov 
anytime. 
Drug Returns: All undispensed drug supplies should be returned to the PMB. When it is 
necessary to return study drug (e.g., sealed bottles remaining when PMB sends a stock 
recovery letter), investigators should return the study drug to the PMB using the NCI 
Return Agent Form available on the NCI home page (http://ctep.cancer.gov). 
Drug Accountability: The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, disposition, and return of 
agent received from the PMB using the NCI Investigational Agent Accountability Record 
Form for Oral Agents available on the NCI home page (http://ctep.cancer.gov). Maintain 
separate NCI Investigational Agent Accountability Records for each agent, strength, 
formulation and ordering investigator. 
Investigator Brochure Availability: The current versions of the IBs for PMB-supplied 
agents will be accessible to site investigators and research staff through the PMB Online 
Agent Order Processing (OAOP) application. Access to OAOP requires the 
establishment of a CTEP Identity and Access Management (IAM) account and the 
maintenance of an “active” account status, a “current” password, and active person 
registration status. Questions about IB access may be directed to the PMB IB 
coordinator at IBCoordinator@mail.nih.gov. 
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5.1
Ipatasertib
5.1.1 
Other Names:  
GDC-0068, R05532961 
5.1.2 
Classification:  
Oral AKT inhibitor 
5.1.3 
Mode of Action:  
Ipatasertib is a potent, selective, ATP-competitive small-molecule 
inhibitor of all three isoforms of AKT. Ipatasertib selectively binds to 
the active conformation of AKT and inhibits its kinase activity. 
5.1.4 
Storage and Stability: 
Storage: Do not store above 25°C / 77°F  
If a storage temperature excursion is identified, promptly return 
ipatasertib to less than 25°C and quarantine the supplies.  Provide a 
detailed report of the excursion (including documentation of 
temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
Stability: Stability studies are ongoing. 
5.1.5 
Dose Specifics:   
Dosing is described in Section 3.1. Starting dose is 400 mg PO QD 
continuously for each 28 day cycle. 
5.1.6 
How Supplied: 
Genentech supplies and CTEP, DCTD, NCI distributes ipatasertib as 
100 mg or 200 mg oval, film-coated tablets in a 30 count bottle. The 
100 mg tablet is greyish yellow and the 200 mg tablet is brownish 
pink. In addition to the ipatasertib drug substance, each tablet 
contains microcrystalline cellulose, pregelatinized maize starch, 
croscarmellose sodium, colloidal silicon dioxide, povidone, 
magnesium stearate and either Opadry II Yellow film coat (100 mg) or 
Opadry II Pink film coat (200 mg). 
5.1.7 
Route of Administration: 
Oral. Ipatasertib can be taken with or without food. 
5.1.8 
Incompatibilities: 
Ipatasertib is primarily metabolized by CYP3A. Strong inhibitors and 
inducers of CYP3A may result increased or decreased ipatasertib 
exposures, respectively. The following drugs should be avoided, or 
used with caution when administering ipatasertib. If using of one of 
these drugs is necessary, the risks and benefits should be evaluated 
prior to its concomitant use with ipatasertib: 
 
Strong CYP3A inhibitors: such as but not limited to atazanavir, 
clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, 
nelfinavir, ritonavir, saquinavir, telithromycin, troleandamycin, 
voriconazole, and/or grapefruit juice or grapefruit supplements 
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Strong CYP3A inducers: such as but not limited to rifampin, 
carbamazepine, rifapentine, phenytoin, phenobarbital, and/or St. 
John’s wort or hyperforin 
 
CYP3A4 substrates with a narrow therapeutic index: such as but 
not limited to alfentanil, astemizole, terfenadine, cisapride, 
cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, 
ergot alkaloids ergotamine, and/or dihydroergotamine 
 
Ipatasertib is a moderate inhibitor of CYP3A4. Sensitive 
substrates with a narrow therapeutic index should be avoided or 
administered with caution. 
5.1.9 
Patient Care Implications 
Because the PI3K-Akt-mTOR pathway is involved in glucose 
metabolism, inhibition of this signaling network and its target mTOR 
can cause hyperglycemia, which is a toxicity common to the class of 
PI3K-Akt-mTOR inhibitors. 
Agents such as proton pump inhibitors (e.g., omeprazole, 
pantoprazole) are not expected to affect ipatasertib PK. 
5.1.10 
Side Effects 
See Section 3.3 for side effects. 
 
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6.
Translational Studies
Please refer to the MATCH Master Protocol for information on the Translational Studies.  
7. 
References 
1. Saura C. A First-in-Human Phase I Study of the ATP-Competitive AKT Inhibitor 
Ipatasertib Demonstrates Robust and Safe Targeting of AKT in Patients with Solid 
Tumors. Cancer Discovery 2017. 2017 Jan;7(1):102-113.  
2. Blake JF.  Discovery and Preclinical Pharmacology of a Selective ATP-Competitive 
Akt Inhibitor (GDC-006) for the Treatment of Human Tumors J Med Chem. 2012 Sep 
27;55(18):8110-27.  
3. Lin. Targeting Activated Akt with GDC-0068, a Novel Selective Akt Inhibitor That is 
Efficacous in Multiple Tumor Models. Clin Cancer Res. 2013 Apr 1;19(7):1760-72.  
4. Hyman DM, et al. AZD5363, a catayltic pan-AKT inhibitior in AKT1 E17K mutation 
positive advanced solid tumors. AACR-NCI-EORTC Conference on Molcular Targets 
and Cancer Therapeutics. November 2015 
5. Mundi. AKT in cancer: new molecular insights and advances in drug development. Br 
J Clin Pharmacol. 2016 Oct;82(4):943-56.  
6. Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem 
1998;67:481-507. 
7. Crowell JA, Steele VE, Fay JR. Targeting the AKT protein kinase for cancer 
chemoprevention. Mol Cancer Ther 2007;6:2139-48. 
8. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of 
AKT/PKB by the rictor-mTOR complex. Science 2005;307:1098-101. 
9. Blanco-Aparicio C, Renner O, Leal JF, Carnero A. PTEN, more than the AKT 
pathway. Carcinogenesis 2007;28:1379-86. 
10. Gottlieb TM, Leal JF, Seger R, Taya Y, Oren M. Cross-talk between AKT, p53 and 
Mdm2: possible implications for the regulation of apoptosis. Oncogene 
2002;21:1299-303. 
11. Dan HC, Ebbs A, Pasparakis M, Van Dyke T, Basseres DS, Baldwin AS. AKT-
dependent activation of mTORC1 complex involves phosphorylation of mTOR 
(mammalian target of rapamycin) by IkappaB kinase alpha (IKKalpha). J Biol Chem 
2014;289:25227-40. 
12. Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance 
across 12 major cancer types. Nature 2013;502:333-9. 
13. Boyault S, Drouet Y, Navarro C, et al. Mutational characterization of individual breast 
tumors: TP53 and PI3K pathway genes are frequently and distinctively mutated in 
different subtypes. Breast Cancer Res Treat 2012;132:29-39. 
14. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, et al. An integrative genomic and 
proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer 
Res 2008;68:6084-91. 
15. Kumar A, Purohit R. Cancer associated E17K mutation causes rapid conformational 
drift in AKT1 pleckstrin homology (PH) domain. PLoS One 2013;8:e64364. 
16. Altomare DA, Testa JR. Perturbations of the AKT signaling pathway in human 
cancer. Oncogene 2005;24:7455-64. 
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17. Banerji S, Cibulskis K, Rangel-Escareno C, et al. Sequence analysis of mutations 
and translocations across breast cancer subtypes. Nature 2012;486:405-9. 
18. Mosquera JM, Varma S, Pauli C, et al. MAGI3-AKT3 fusion in breast cancer 
amended. Nature 2015;520:E11-2. 
19. Hammond MEH, Hayes DF, Dowsett M, et al. American Society of Clinical   
Oncology/College of American Pathologists guideline recommendations for 
immunohistochemical testing of estrogen and progesterone receptors in breast 
cancer. J Clin Oncol. 2010;28:2784. 
20. Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, Allred 
DC, Bartlett JMS, Bilous M, Fitzgibbons P, Hanna W, Jenkins RB, Mangu PB, Paik 
S, Perez EA, Press MF, Spears PA, Vance GH, Viale G, Hayes DF. 
Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast 
Cancer: American Society of Clinical Oncology/College of American Pathologists 
Clinical Practice Guideline Update. J Clin Oncol. 2013;31(31):3997-4013. 
21. Busaidy NL, Farooki A, Dowlati A, et al. Management of Metabolic Effects 
Associated with Anticancer Agents Targeting the PI3K-Akt-mTor Pathway. J Clin 
Oncol. 2012; 30 (23): 2919-2928. 
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Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol Z1K:  
Ipatasertib in Patients with Tumors with AKT Mutations 
Appendix I 
 
Patient Pill Calendar 
Storage: Store at Room Temperature 
Pill Calendar Directions 
22. Take your scheduled dose of each tablet at the same time each day. 
23. Please bring the empty bottle or any leftover tablets and your pill calendar to your 
next clinic visit. 
24. All doses of Ipatasertib can be taken with or without food.  
25. Ipatasertib is to be taken orally once daily. 
26. If you vomit later than 30 minutes after Ipatasertib dosing, do not retake new 
tablet(s), but continue to take the next dose 24 hours later. 
27. If you miss a dose, you may take the dose up to a maximum of 8 hours after the 
scheduled dose time. If greater than 8 hours after the scheduled dose time, the 
missed dose should not be made up.  
28. If you need to take the dose earlier for whatever reason, you can take the dose up to 
8 hours earlier than the scheduled dose time.  
 
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ECOG-ACRIN
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Version Date: November 10, 2022 
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Patient Pill Calendar
This is a calendar on which you are to record the time and number of tablets you take each day. 
You should take your scheduled dose of each tablet. Note the times and the number of 
tablets that you take each day. If you develop any side effects, please record them and 
anything you would like to tell the doctor in the space provided.  Bring any unused tablets and 
your completed pill calendar to your doctor’s visits. 
Patient ID: __________________    
Cycle: ___ Dose Information: ____________________________________________________ 
 
Ipatasertib 
DAY 
Date 
Time tablets 
taken 
Number of 
tablets taken 
(100 mg) 
Number of 
tablets taken 
(200 mg) 
Use the space below to 
make notes about things 
you would like to tell the 
doctor (including unusual 
symptoms you 
experience, other 
medicine you have taken 
and anything else you 
think would be of 
interest.) 
Month Day 
Year 
 
 
 
 
 
 
1 
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
9 
10
11
12 
 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
 
19 
 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
 
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Version Date: November 10, 2022 
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DAY 
Date 
Time tablets 
taken 
Number of 
tablets taken 
(100 mg) 
Number of 
tablets taken 
(200 mg) 
Use the space below to 
make notes about things 
you would like to tell the 
doctor (including unusual 
symptoms you 
experience, other 
medicine you have taken 
and anything else you 
think would be of 
interest.) 
Month Day
Year
21
22
23
24
25
26 
 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
Patient Signature: _________________________________________ Date: _____________ 
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Use of this document is governed by the terms of use on the first page of this document.

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Use of this document is governed by the terms of use on the first page of this document.

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ECOG-ACRIN
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Version Date: November 10, 2022 
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Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol Z1K:  
Ipatasertib in Patients with Tumors with AKT Mutations 
Appendix III 
 
CYP3A4/5 Strong Inducers and Potent Inhibitors 
Because the lists of these agents are constantly changing, it is important to regularly 
consult a frequently-updated list such as Facts and Comparisons or Lexicomp; medical 
reference texts such as the Physicians’ Desk Reference may also provide this 
information. Another reference is the Drug Development and Drug Interactions: Table of 
Substrates, Inhibitors and Inducers: 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugI
nteractionsLabeling/ucm093664.htm 
The Principal Investigator should be alerted if the subject is taking any agent on these 
lists. Appropriate medical judgment is required. 
CYP3A4/5 Potent Inhibitors: 
Ketoconazole 
 
Mebefradil 
Protease inhibitors (danoprevir, ritonavir, 
Itraconazole 
saquinavir, indanavir, tapranavir, 
 
Posaconazole 
telaprevir, elvitegravir, lopinavir, 
 
Voriconazole 
nelfinavir, bocepravir) 
 
Clarithromycin 
Cobicistat 
 
Telithromycin 
Conivaptan 
 
Troleandomycin 
Nefazodone 
 
 
CYP3A4/5 Inducing Agents: 
Phenobarbital 
 
Rifabutin 
Carbamazepine  
 
Mitotane 
Phenytoin 
Rifampicin 
Grapefruit or Grapefruit supplements 
St John’s Wort 
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AKT inhibitors in development:
Drug:  
Company 
Alt. Names 
Targets 
MK-2206 
Merck 
 
Pan-AKT isoforms 
GSK-690693 
GlaxoSmithKline 
 
Pan-AKT isoforms 
AZD5363 
AstraZeneca 
 
Pan-AKT isoforms 
KRX-0401 
Keryx 
perifosine 
Dual AKT and PI3K inhibitor 
DNE3 
 
 
Pan-AKT isoforms 
ONC-201 
Oncoceutics 
 
Dual AKT and ERK inhibitor 
BAY-1125976 
Bayer 
 
AKT1,2  
GSK-2141795 
GlaxoSmithKline 
uprosertib 
Pan-AKT isoforms 
GSK-2110183 
GlaxoSmithKline 
afuresertib  
Pan-AKT isoforms 
SR-13668 
 
 
AKT, 12-LOX 
MSC-2363318A 
Merck Serono 
 
Dual p70S6K/pan-AKT inhibitor 
LY-2780301 
Lilly 
 
Dual p70S6K/pan-AKT inhibitor 
VD-0002 
Vioquest 
triciribine 
Pan-AKT isoforms 
AG1343 
 
nelfinavir; 
Viracept 
HIV protease inhibitor, AKT 
miltefosine 
 
Impavido 
AKT, PI3K, PKC  
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ECOG-ACRIN
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Molecular Analysis for Therapy Choice (MATCH)
MATCH Treatment Subprotocol Z1K:  
Ipatasertib in Patients with Tumors with AKT Mutations
Appendix V
PATIENT DRUG INTERACTIONS HANDOUT AND WALLET CARD
Information for Patients, Their Caregivers and Non-Study Healthcare Team on Possible 
Interactions with Other Drugs and Herbal Supplements
Patient 
Name:
     
Diagnosis: 
      
Trial #:
     
t dy 
Doctor:
     
Study Doctor 
Phone #:
     
Study 
Drug(s):
Ipatasertib
Please show this paper to all your healthcare providers (doctors, physician assistants, nurse 
practitioners, pharmacists), and tell them you are taking part in a clinical trial sponsored by the 
National Cancer Institute. 
These are the things that your healthcare providers need to know:
Ipatasertib interacts with certain specific enzymes in your liver and certain transport proteins 
that help move drugs in and out of cells.
Explanation
CYP 
isoenzymes  
The enzyme in question is CYP3A4. Ipatasertib is metabolized by CYP3A4 and may 
be affected by other drugs that inhibit or induce this enzyme. Ipatasertib is an inhibitor 
of CYP3A4 and may affect the metabolism of other drugs.
These are the things that you need to know: 
The study drug, ipatasertib, may interact with other drugs which can cause side effects. For this 
reason, it is very important to tell your doctors about all your medicines, including: (a) medicines 
you are taking before this clinical trial, (b) medicines you start or stop taking during this study, 
(c) medicines you buy without a prescription (over-the-counter remedy), (d) herbals or 
supplements (e.g. St. John’s Wort). It is helpful to bring your medication bottles or an updated 
medication list with you. 
Before you enroll onto the clinical trial, your study doctor will work with your regular health care 
providers to review any medicines and herbal supplements that are considered “strong inhibitors 
or inducers of CYP3A4 or sensitive substrates of CYP3A4.”
Please be very careful! Over-the-counter drugs (including herbal supplements) may contain 
ingredients that could interact with your study drug. Speak to your doctors or pharmacist to 
determine if there could be any side effects.
Avoid ingestion of grapefruit, grapefruit juice or grapefruit supplements.
Make sure your doctor knows to avoid certain prescription medications. 
Your regular health care provider should check a frequently updated medical reference or 
call your study doctor before prescribing any new medicine or discontinuing any medicine.
Rev. Add25
S
D
Rev. Add31
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