A Phase 1, Open-Label, Dose-Escalation With Expansion Study of SX-682 in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab

SX-682 Treatment in Subjects With Metastatic Melanoma Concurrently Treated With Pembrolizumab



Sponsors


Source

Syntrix Biosystems, Inc.

Oversight Info

Has Dmc

No

Is Fda Regulated Drug

Yes

Is Fda Regulated Device

No


Brief Summary

Cancers attract myeloid-derived suppressor cells (MDSCs) that prevent our own immune
responses from destroying the cancer. This study will be the first study to begin to
determine if the newly discovered drug SX-682 can block cancers from attracting MDSCs. This
first study will enroll participants with melanoma, as melanoma cancer has been shown to be
able to attract MDSCs. The study will begin to determine if SX-682 is a safe and effective
treatment of melanoma. It is thought that SX-682 will block MDSCs from going to the cancer,
and thus will allow a patient's own immune system to attack the cancer.

The first participants enrolled in the study will receive for 21 days SX-682 as monotherapy.
After 21 days participants will receive pembrolizumab therapy (an approved immunotherapy for
melanoma) and will remain in the study for evaluations for 3 months.

After these participants complete the monotherapy stage, the next participants will receive
SX-682 and pembrolizumab together as combination therapy. These participants will receive
the combination therapy and be evaluated in the study for approximately 2 years.

Detailed Description

Objectives

The primary objective is to determine the safety profile of SX-682 alone and in combination
with pembrolizumab in subjects with metastatic melanoma, including the maximum dose that can
be administered until adverse effects prevent further dose increases, and the dose-limiting
toxicity (DLT).

The secondary objectives are to: 1) evaluate the efficacy of SX-682 in combination with
pembrolizumab on the basis of the objective response rate, the duration of response, and the
rate of progression; and 2) characterize the SX-682 single-dose and multidose PK profile.

Exploratory objectives are to: 1) assess overall survival (OS); and 2) explore potential
biomarkers associated with pharmacodynamic and clinical response to SX-682 alone and
combined with pembrolizumab, where the biomarker measures include, but are not limited to,
tumor myeloid-derived suppressor cells (MDSC), Tregs and CD69/CD8 T cells, and in the
circulation, T- and B-cell subpopulations, neutrophils, the neutrophil-to-lymphocyte ratio
(NLR), Tregs, the CD4:CD8 ratio, chemokines, cytokines, and LDH.

Overview of Study Design

This is a Phase 1, open-label, single-center, dose-escalation with expansion study of
twice-daily SX-682 in subjects with metastatic melanoma treated concurrently with
pembrolizumab (Combination Stage) following a 21 day dose-escalation safety evaluation of
SX-682 monotherapy (Monotherapy Stage). SX-682 is an oral small-molecule inhibitor of the
CXCR1/2 chemokine receptors that are believed involved in MDSC-recruitment to tumor and
other pro-tumoral mechanisms. Dosing of SX-682 in the Combination Stage is conditioned on
ongoing concurrent treatment with pembrolizumab, and a subject who discontinues
pembrolizumab may not receive further doses of SX-682.

Overall Status

Not yet recruiting

Start Date

2017-12-01

Completion Date

2020-12-01

Primary Completion Date

2020-08-01

Phase

Phase 1

Study Type

Interventional

Primary Outcome

Measure

Time Frame

SX-682 Maximum Tolerated Dose (MTD) during Monotherapy Stage
Up to 21 Days in 21 day Cycle 1 of Monotherapy Stage.
SX-682 Maximum Tolerated Dose during Combination Therapy Stage
Up to 42 Days in 42 day Cycle 1 of Combination Therapy Stage.
The observed tumor response rate
Days 38-42 of each 42 day Combination Stage cycle (Cycles 1-17)
The observed tumor response duration
Days 38-42 of each 42 day Combination Stage cycle (Cycles 1-17)
Progression free survival
Days 38-42 of each 42 day Combination Stage cycle (Cycles 1-17)
Overall survival
Combination Stage cycle (Cycles 1-17) and the 90 day follow-up period after the last SX-682 dose.

Secondary Outcome

Measure

Time Frame

SX-682 dose limiting toxicities (DLTs) during monotherapy
Up to 21 Days in 21 day Cycle 1.
SX-682 dose limiting toxicities (DLTs) during combination therapy stage
Days 38-42 of each 42 day Combination Stage cycle (Cycles 1-17).
Adverse events during Monotherapy Stage
Up to 21 Days in 21 day Cycle 1 of monotherapy stage.
Adverse events during combination Therapy Stage
Up to 42 Days in 42 day Cycle 1-17 of Combination Therapy Stage.
SX-682 single dose pharmacokinetic parameters during SX-682 monotherapy and SX-682 and pembrolizumab combination therapy
SX-682 dose on Day 1 of Cycle 1 of Monotherapy Stage and Combination Therapy Stage.
SX-682 steady-state pharmacokinetic parameters during SX-682 monotherapy and SX-682 and pembrolizumab combination therapy
Morning dose of day 15 of Cycle 1 of monotherapy stage and combination therapy stage.

Enrollment

77

Conditions


Intervention

Intervention Type

Drug

Intervention Name


Description

SX-682 is an oral small molecule selective inhibitor of C-X-C Motif Chemokine Receptor 1 (CXCR1) and C-X-C Motif Chemokine Receptor 2 (CXCR2)

Arm Group Label

Monotherapy: SX-682 dose escalation

Combination therapy: SX-682 dose escalation and pembrolizumab



Intervention Type

Biological

Intervention Name


Description

Pembrolizumab is a humanized antibody that targets the programmed cell death 1 receptor (PD-1).

Arm Group Label

Combination therapy: SX-682 dose escalation and pembrolizumab

Other Name

KEYTRUDA



Eligibility

Criteria

Inclusion Criteria:

- Subjects must have the nature of the study explained to them.

- Subjects must be willing and able to comply with scheduled visits, treatment
schedule, laboratory tests, pharmacokinetic collections, and other requirements of
the study.

- Subjects must provide a signed and dated IRB/IEC approved written informed consent
form (ICF) in accordance with regulatory and institutional guidelines.

- Subjects must provide a signed and dated Health Insurance Portability and
Accountability Act (HIPAA) authorization.

- The ICF and HIPAA authorization must be obtained before conducting any procedures
that do not form a part of the subject's normal care.

- After signing the ICF and HIPAA Authorization, subjects will be evaluated for study
eligibility during the Screening Period (no more than 28 days before study drug
administration) according to the following further inclusion/exclusion criteria:

- Histologically confirmed unresectable Stage III or Stage IV melanoma as per AJCC
staging system.

- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

- No prior systemic anticancer therapy for unresectable or metastatic melanoma. Note
that prior adjuvant or neoadjuvant melanoma therapy is permitted if it was completed
at least 6 weeks prior to first dose, and all related adverse events have either
returned to baseline or stabilized.

- Must have measurable disease with at least 1 unidimensional measurable lesion per
RECIST v1.1.

- Pre-treatment tumor tissue (i.e., archived paraffin-embedded) obtained in the
metastatic setting or from an unresectable site of disease must be available for
biomarker analyses. Biopsy should be excisional, incisional punch or core needle.
Fine needle aspirates or other cytology samples are insufficient.

- Known BRAF V600 mutation status; subjects with either V600 wild-type or V600
mutation-positive status are eligible.

- Prior radiotherapy must have been completed at least 2 weeks prior to study drug
administration.

- Screening laboratory values must meet the following criteria and should be obtained
within 14 days prior to first dose:

WBC ≥ 3000/µL Neutrophils ≥ 1500/ µL Platelets ≥ 100,000/µL Hemoglobin ≥ 9.0 g/dL (may
have been transfused) Creatinine ≤ 1.5 mg/dL AST/ALT ≤ 2.5 X ULN for subject with no liver
metastases

- 5 X ULN for subjects with liver metastases Bilirubin < 1.5 mg/dL (unless diagnosed
with Gilbert's syndrome,who can have total bilirubin < 3.0 mg/dL) INR or PT ≤ 1.5 X
ULN unless the subject is receiving anticoagulant therapy aPTT or PTT ≤ 1.5 X ULN
unless the subject is receiving anticoagulant therapy

- No known positivity for human immunodeficiency virus (HIV) (no laboratory
testing is required), no active infection with Hepatitis B or Hepatitis C.

- Life expectancy > 12 weeks.

- Subject Re-enrollment: This study permits the re-enrollment of a subject that
has discontinued the study as a pre-treatment failure (i.e., subject has not
been treated with SX-682) after obtaining agreement from the medical monitor
prior to re-enrolling a subject. If re-enrolled, the subject must be
re-consented.

- Men and women, ages > 18 years of age.

- Women of childbearing potential (WOCBP) must use method(s) of contraception (as
will be explained in detail) while on study and for 4 months after the last dose
of SX-682 or pembrolizumab. A WOCBP is defined as any female who has experienced
menarche and who has not undergone surgical sterilization (hysterectomy or
bilateral oophorectomy) or is not postmenopausal. Menopause is defined
clinically as 12 months of amenorrhea in a woman over age 45 in the absence of
other biological or physiological causes.

- Women under the age of 62 with a history of being postmenopausal must have a
documented serum follicle stimulating hormone, (FSH) level > 40 mIU/mL.

- Women must have a negative serum or urine pregnancy test (minimum sensitivity 25
IU/L or equivalent units of HCG) within 24 hours prior to the start of study
drug.

- Women must not be breastfeeding.

- Men who are sexually active with WOCBP must use any contraceptive method with a
failure rate of less than 1% per year while on study and for a period at least 6
months after the last dose of study drug.

- Women who are not of childbearing potential and azoospermic men do not require
contraception.

Exclusion Criteria:

- Active brain metastases or leptomeningeal metastases. Subjects with brain metastases
are eligible if these have been treated and there is no magnetic resonance imaging
(MRI - except where contraindicated, in which CT scan is acceptable) evidence of
progression for at least 8 weeks after treatment is complete and within 28 days prior
to first dose of study drug administration. There must also be no requirement for
high doses of systemic corticosteroids that could result in immunosuppression (> 10
mg/day prednisone equivalents) for at least 2 weeks prior to study drug
administration.

- Ocular melanoma.

- Subject was randomized into a prior pembrolizumab trial.

- Any serious or uncontrolled medical disorder that, in the opinion of the
investigator, may increase the risk associated with study participation or study drug
administration, impair the ability of the subject to receive protocol therapy, or
interfere with the interpretation of study results. Specifically:

Subjects with active, non-infectious pneumonitis. Subjects with interstitial lung disease
or a history of pneumonitis that required oral or intravenous glucocorticoids to assist
with management.

Subjects with clinically significant heart disease that affects normal activities.

- Prior malignancy active within the previous 3 years except for locally curable
cancers that have been apparently cured, such as basal or squamous cell skin cancer,
superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.

- Subjects with active, known or suspected autoimmune disease (Appendix 3). Subjects
with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune
condition only requiring hormone replacement, psoriasis not requiring systemic
treatment, or conditions not expected to recur in the absence of an external trigger
are permitted to enroll.

- Subjects with a condition requiring systemic treatment with either corticosteroids (>
10 mg daily prednisone equivalents) or other immunosuppressive medications within 14
days of study drug administration. Inhaled or topical steroids, and adrenal
replacement doses > 10 mg daily prednisone equivalents are permitted in the absence
of active autoimmune disease.

- Prior treatment with an anti-PD1, anti-PD-L1, anti-PD-L2, anti-CTLA4 antibody, or any
other antibody or drug specifically targeting T-cell costimulation or immune
checkpoint pathways.

- Use of other investigational drugs (drugs not marketed for any indication) within 30
days before study drug administration.

- Subjects who have had major surgery in the past 4 weeks.

- Subjects who have received a live-virus vaccine within 30 days before study drug
administration.

- Any positive test for hepatitis B virus or hepatitis C virus indicating acute or
chronic infection.

- Known history of testing positive for human immunodeficiency virus (HIV) or known
acquired immunodeficiency syndrome (AIDS).

- History of allergy to study drug components.

- History of severe hypersensitivity reaction to any monoclonal antibody

- Women of childbearing potential who are pregnant or breastfeeding.

- Women with a positive pregnancy test at enrollment or prior to administration of
study medication.

- Prisoners or subjects who are involuntarily incarcerated, or other vulnerable
populations (study is exempt from 45 CFR 46 Subparts B, C, and D).

- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (e.g., infectious disease) illness

Gender

All

Minimum Age

18 Years

Maximum Age

N/A

Healthy Volunteers

No


Overall Official

Last Name

Role

Affiliation

Keith T. Flaherty, M.D.
Principal Investigator
Massachusettes General Hospital Cancer Center

Overall Contact

Last Name

Keith T Flaherty, M.D.

Phone

617-724-4000

Email

[email protected]


Location

Facility

Massachusettes General Hospital Cancer Center
Boston Massachusetts 02114 United States

Location Countries

Country

United States


Verification Date

2017-05-01

Lastchanged Date

2017-05-18

Firstreceived Date

2017-05-16

Responsible Party

Responsible Party Type

Sponsor


Keywords


Has Expanded Access

No

Condition Browse


Secondary Id

1R44CA217591-01

Number Of Arms

2

Intervention Browse

Mesh Term

Pembrolizumab


Arm Group

Arm Group Label

Monotherapy: SX-682 dose escalation

Arm Group Type

Experimental

Description

Escalating oral doses of SX-682 (study drug) of 25, 50, 100, 200 and 400 mg twice-daily (i.e., 50, 100, 200, 400 and 800 mg total each day.


Arm Group Label

Combination therapy: SX-682 dose escalation and pembrolizumab

Arm Group Type

Experimental

Description

SX-682 will be initiated at an initial SX-682 dose no more than 50% of the single-agent MTD/RP2D and will be administered in a 6 week cycle that includes 2 i.v. infusions of pembrolizumab (2 mg/kg) on days 1 and 22 of each cycle, for a total of up to 17 cycles. Once the highest safe dose of SX-682 is determined participants will be enrolled at that dose for combination therapy.



Firstreceived Results Date

N/A

Patient Data

Sharing Ipd

No


Firstreceived Results Disposition Date

N/A

Study Design Info

Allocation

Non-Randomized

Intervention Model

Sequential Assignment

Intervention Model Description

In this sequential model initially participant groups will enroll to receive SX-682 monotherapy for 21 days in a dose escalation phase. A 3 + 3 participant design will be used to determine the safe dose. After 21 days, at the specified dose of SX-682, SX-682 therapy will be stopped and participants will receive pembrolizumab therapy and continue to be evaluated for 90 days.
After the safe dose of SX-682 monotherapy has been determined, subjects will be enrolled to receive SX-682 and pembrolizumab combination therapy, in a SX-682 dose escalation phase. Again, a 3 + 3 participant design will be used to determine the safe dose. The next higher dose level will be enrolled only after subjects have received the current dose level safely for at least 6 weeks.
Once the safe dose level of SX-682 in combination with pembrolizumab is determined, then participants will be enrolled at the highest safe dose level of SX-682, in combination with pembrolizumab, in an expansion phase.

Primary Purpose

Treatment

Masking

No masking



ClinicalTrials.gov processed this data on May 19, 2017

Conditions

Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov, conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions

Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase

Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:

In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.



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