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Neoplastic Processes

CC-90003 by mouth (PO) daily on days 1 -21 of every 28 day cycle; Cycle 1, Days 1 to 28 will constitute the dose limiting toxicity (DLT) assessment period for purposes of non-tolerated dose (NTD) and Maximum Tolerated Dose determination.

CC-90003

Gordon Bray, MD

The CC-90003-ST -001 trial is a first-in-man, open-label study in subjects with locally-advanced or wide spread cancers to determine if CC-90003 (an oral medication) can be adequately tolerated with minimal side effects.

CC-90003-ST -001 is an open-label, multicenter, Phase 1a study in subjects with locally-advanced or metastatic, solid tumors who are intolerant of, resistant to, or have relapsed after at least one line of therapy and for whom no standard therapy exists. The study will be conducted in two parts: Dose Escalation (Part 1) and Cohort Expansion (Part 2). Subjects may continue CC-90003 until progression of their underlying malignancy, the occurrence of intolerable toxicity, or physician/subject decision to discontinue CC-90003. In Part 1, cohorts of subjects with relapsed or refractory solid tumors will receive increasing doses of CC-90003 in order to assess its safety and tolerability, the maximum tolerated dose (MTD), and PK profile. In Part 2, cohorts of subjects with specific tumors that harbor mutations involving the Mitogen -Activated Protein Kinase (MAPK) pathway will receive CC-90003 at or below the MTD until progression of disease, intolerable toxicity, or physician/subject decision to discontinue CC-90003.

Safety and PK Study of CC-90003 in Relapsed/Refractory Solid Tumors

A Phase 1a Multicenter, Open-label Safety, Tolerability and Pharmacokinetic Study of CC-90003, a Selective Extracellular Signal-Regulated Kinase (ERK) Inhibitor, in Subjects With Locally-Advanced or Metastatic, Relapsed, or Refractory BRAF or RAS-Mutated Malignancies

An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values regardless of etiology.

Number of participants with dose limiting toxicities during the Dose Escalation Phase

The MTD is defined as the highest dose level at which no more than 1 in 6 participants experiences a dose- limiting toxicity (DLT) during the first 28 day cycle of treatment

The maximally observed plasma concentration of CC-90003 (Cmax)

Area under the plasma concentration -time curve of CC-90003

Terminal phase elimination half-life (t1/2) is calculated as follows: t1/2 =ln(2)/λz, where λz is the first order rate constant associated with the terminal portion of the CC-90003 plasma concentration curve

The apparent total body clearance of CC-90003 from plasma

PK- Apparent Total Volume of Distribution (Vz/F) During the terminal phase for CC- 90003

Accumulation represents the relationship between the dosing interval and the rate of elimination for the drug

The proportion of subjects who achieve a best response of CR or PR.

Duration of response is the time from the start of study treatment until the first documentation of an objective response (either CR or PR).

The proportion of subjects who achieve a best response of SD (documented at least 56 days after the start of study treatment) PR, or CR

PFS is defined as the time from the start of study treatment until progression (PD) or patient death (any cause), whichever occurs first

Overall survival is defined as the time from start of study treatment until the date of death from any cause.

Celgene

DCC-2701 tablets in escalating dose cohorts given orally BID (twice daily) every 12 hours for a 28-day cycle. Participants may continue to receive study drug until discontinuation criteria are met.

DCC-2701 tablet

Oliver Rosen, M.D.

The main purpose of this study is to investigate the safety of the investigational drug DCC-2701 and whether it will work to help people who have advanced solid tumors or cancer that has spread to other parts of the body.

This is a first-in-human study of DCC-2701. The primary purpose of this study is to determine what dose of DCC-2701, can be given safely to patients with advanced solid tumors.

The study will have two phases. The first phase will assess escalating doses of DCC-2701 in order to determine the maximally tolerated dose (MTD) and the optimal dosing regimen (ODR) of DCC-2701. Once the MTD and ODR is established, a dose expansion phase will further evaluate the safety of DCC-2701, as well as the activity of DCC-2701 in select solid tumor types.

A Study of DCC-2701 in Participants With Advanced Solid Tumors

A Multicenter Phase 1 Ascending Dose Study of DCC-2701 To Assess Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics in Patients With Advanced Solid Tumors

Deciphera Pharmaceuticals LLC

Participants receive 30 mg oral MK-2206 every other day (QOD) in repeating 4-week treatment cycles.

Participants receive 60 mg oral MK-2206 QOD in repeating 4-week treatment cycles.

Participants receive 75 mg oral MK-2206 QOD in repeating 4-week treatment cycles.

Participants receive 90 mg oral MK-2206 QOD in repeating 4-week treatment cycles.

Participants receive 90 mg oral MK-2206 every week (QW) in repeating 4-week treatment cycles.

Participants receive 135 mg oral MK-2206 QW in repeating 4-week treatment cycles.

Participants receive 200 mg oral MK-2206 QW in repeating 4-week treatment cycles.

Participants receive 300 mg oral MK-2206 QW in repeating 4-week treatment cycles.

Participants receive 250 mg oral MK-2206 QW in repeating 4-week treatment cycles.

Participants receive 150 mg oral MK-2206 QW in repeating 4-week treatment cycles.

MK-2206 administered as an oral formulation in rising dose levels on a QOD schedule (30 mg, 60 mg, 75 mg, and 90 mg) or QW schedule (90 mg, 135 mg, 200 mg, 250 mg, and 300 mg) in repeating 4 week cycles, depending upon allocation.

MK-2206

Medical Monitor

The primary purpose of this study is to investigate the Dose Limiting Toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics (PD) of MK-2206 administered orally to participants with advanced solid tumors. The preliminary efficacy of MK-2206 will also be investigated.

Dose Escalation Study With MK-2206 in Patients With Locally Advanced or Metastatic Solid Tumors (MK-2206-002)

A Phase I Dose Escalation Study of Oral MK-2206 in Patients With Locally Advanced or Metastatic Solid Tumors

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

DLT was any drug-related AE, regardless of grade, leading to a dose modification of MK-2206. Dose-limiting hematologic and nonhematologic toxicities were defined differently and were based on events occurring during the first cycle of study drug administration. Hematologic DLT defined as any Grade (Gr) 4 or greater hematologic toxicity except neutropenia described as follows: Neutropenia that was Gr 4 lasting for ≥7 days, or Gr 3/Gr 4 with fever \>38.5°C and/or infection requiring antibiotic or anti-fungal treatment considered DLT. Gr 4 thrombocytopenia (≤25.0 x 10\^9/L) was also considered DLT. Non-hematologic DLTs were defined as any Gr 3, 4, or 5 nonhematologic toxicity, with the specific exceptions of: Gr 3 nausea, vomiting, diarrhea, or dehydration occurring with inadequate supportive care and lasting \<48 hours; alopecia; inadequately treated hypersensitivity reactions; and Gr 3 elevated transaminases of ≤1 week in duration. A participant could have more than one DLT.

An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition which was temporally associated with the use of the SPONSOR's product, was also an AE. The number of participants that experienced one or more AEs was reported for each dose level group.

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. AUC 0-48hr was calculated for Day 1 and the last day of treatment in Cycle 1 (Day 27) and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. Cmax was calculated for Day 1 and the last day of treatment in Cycle 1 (Day 27) and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. C48hr was calculated for Day 1 and the last day of treatment in Cycle 1 (Day 27) and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. Tmax was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).

Blood samples were collected for PK analyses on Day 27 of the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. t½ (Harmonic mean ± pseudo SD) was calculated and reported for all dose levels receiving MK-2206 orally QOD (30, 60, 75, and 90 mg QOD).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. AUC 0-168 was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. Cmax was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. C48hr was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. Tmax was calculated for Day 1 and the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).

Blood samples were collected for PK analyses during the first cycle of therapy. Samples were centrifuged, plasma was withdrawn and plasma concentrations were analyzed by high performance liquid chromatography with tandem mass spectroscopy. t½ (Harmonic mean ± pseudo SD) was calculated for the last day of treatment in Cycle 1 and reported for all dose levels receiving MK-2206 orally QW (90, 135, 200, 300, 250, and 150 mg QW).

To determine the inhibition of pAkt by MK-2206 in participants treated at the MTD, levels of Akt phosphorylated at the serine 473 residue (pAkt Ser473 Akt) were measured in snap-frozen tumors collected at baseline and Day 15 of Cycle 1 using a MesoScale enzyme-linked immunosorbent assay (ELISA). Per protocol, pAkt levels were determined only for the MK-2206 MTD (60 mg QOD) group.

Overall tumor response was assessed during the study by diagnostic anatomic imaging using RECIST. The number of participants with a confirmed Complete Response (CR: Disappearance of all target lesions) as per RECIST was reported for each dose level group.

Merck Sharp & Dohme LLC

APaT population: All participants who received at least one dose of study treatment.

MK-2206 30 mg QOD

MK-2206 60 mg QOD

MK-2206 75 mg QOD

MK-2206 90 mg QOD

MK-2206 90 mg QW

MK-2206 135 mg QW

MK-2206 200 mg QW

MK-2206 300 mg QW

MK-2206 250 mg QW

MK-2206 150 mg QW

Total

Age, Continuous

Sex: Female, Male

Senior Vice President, Global Clinical Development

Hyperglycaemia

Rash

Rash macular

Stomatitis

Diarrhoea

Pruritis

Rash generalized

Dermatitis acneiform

Total number of participants with DLTs

The All Participants as Treated (APaT) population: All participants who received at least one dose of study treatment.

Number of Participants With Dose Limiting Toxicities (DLTs)

Number of Participants With One or More Adverse Events (AE)

The Last Day (Day 27)/Day 1 AUC 0-48 hr Geometric Mean Ratio (GMR) was calculated as follows: Last Day (Day 27) AUC 0-48hr Geometric Mean (GM) ÷ Day 1 AUC 0-48hr GM.

AUC 0-48hr GMR for last dose (Day 27) calculated using only data from participants who completed cycle one dosing as scheduled and had sufficient data for calculation.

The Last Day (Day 27)/Day 1 AUC 0-48 hr GMR was calculated as follows: Last Day (Day 27) AUC 0-48hr GM ÷ Day 1 AUC 0-48hr GM.

AUC 0-48hr GMR for last dose (Day 27) calculated using only data from participants who completed cycle one dosing as scheduled and had sufficient data for calculation.

Day 1

Last Day (Day 27)

All participants who received MK-2206 orally QOD during Cycle 1 (30, 60, 75, and 90 mg QOD) and had available PK data. Data for the MK-2206 QW dose groups (90, 135, 200, 300, 250, and 150 mg QW) are reported separately.

Area Under the Concentration-time Curve of MK-2206 From Time 0 to 48 Hours (AUC0-48hr) in Participants Receiving Multiple QOD Dosing

The Last Day (Day 27)/Day 1 Cmax GMR was calculated as follows: Last Day (Day 27) Cmax GM ÷ Day 1 Cmax GM.

Cmax GMR for last dose (Day 27) calculated using only data from participants who completed cycle one dosing as scheduled and had sufficient data for calculation.

Maximum Concentration (Cmax) of MK-2206 in Participants Receiving Multiple QOD Dosing

The Last Day (Day 27)/Day 1 C48hr GMR was calculated as follows: Last Day (Day 27) C48hr GM ÷ Day 1 C48hr GM.

C48hr GMR for last dose (Day 27) calculated using only data from participants who completed cycle one dosing as scheduled and had sufficient data for calculation.

Concentration of MK-2206 After 48 Hours (C48hr) in Participants Receiving Multiple QOD Dosing

Time to Maximum Concentration (Tmax) of MK-2206 in Participants Receiving Multiple QOD Dosing

All participants who received MK-2206 orally QOD on Day 27 of Cycle 1 (30, 60, 75, and 90 mg QOD) and had available PK data. Data for the MK-2206 QW dose groups (90, 135, 200, 300, 250, and 150 mg QW) are reported separately.

Apparent Terminal Half-life (t½) of MK-2206 in Participants Receiving Multiple QOD Dosing

The Last Day/Day 1 AUC 0-168 hr GMR was calculated as follows: Last Day AUC 0-168hr GM ÷ Day 1 AUC 0-48hr GM.

Last Day (Day 22)

All participants who received MK-2206 orally QW during Cycle 1 (90, 135, 200, 300, 250, and 150 mg QW) and had available PK data. Data for the MK-2206 QOD dose groups (30, 60, 75, and 90 mg QOD) are reported separately.

AUC0-168hr in Participants Receiving Multiple QW Dosing

The Last Day/Day 1 Cmax GMR was calculated as follows: Last Day Cmax GM ÷ Day 1 Cmax GM.

Cmax of MK-2206 in Participants Receiving Multiple QW Dosing

The Last Day/Day 1 C48hr GMR was calculated as follows: Last Day C48hr GM ÷ Day 1 C48hr GM.

C48hr of MK-2206 in Participants Receiving Multiple QW Dosing

Tmax of MK-2206 in Participants Receiving Multiple QW Dosing

All participants who received MK-2206 orally QW on Day 22 of Cycle 1 (90, 135, 200, 300, 250, and 150 mg QW) and had available PK data. Data for the MK-2206 QOD dose groups (30, 60, 75, and 90 mg QOD) are reported separately.

t½ of MK-2206 in Participants Receiving Multiple QW Dosing

pAkt Geometric Mean Ratio (GMR)

= Day 15 Geometric Mean (GM) ÷ Baseline GM

Baseline

Cycle 1 Day 15

Participants treated at the MTD (60 mg QOD) dose level with measurable disease at baseline per RECIST and paired tumor samples at baseline and C1D15. Per protocol, no other dose level groups were analyzed.

Phosphorylated Protein Kinase B (pAkt) Level on Cycle 1 Day 15 (C1D15) After Treatment With MK-2206 at the Maximum Tolerated Dose (MTD)

All participants with measurable disease at baseline per RECIST.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and PK Study of CC-90003 in Relapsed/Refractory Solid Tumors	NCT02313012	Neoplasm Metast...	CC-90003	18 Years -	Celgene
A Study of DCC-2701 in Participants With Advanced Solid Tumors	NCT02228811	Locally Advance... Metastatic Soli... Cancers With ME... Cancers With TR...	DCC-2701 tablet	18 Years -	Deciphera Pharmaceuticals LLC
Dose Escalation Study With MK-2206 in Patients With Locally Advanced or Metastatic Solid Tumors (MK-2206-002)	NCT00670488	Locally Advance... Metastatic Soli... Cancer Neoplasms	MK-2206	18 Years -	Merck Sharp & Dohme LLC

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