This dose-escalation study will evaluate the safety, tolerability, pharmacokinetics, and
pharmacodynamics of IPI-549 monotherapy and IPI-549 in combination with nivolumab in subjects
with advanced solid tumors.
Study IPI-549-01 is a first-in-human multicenter, open-label, up to five-part Phase 1/1b
dose-escalation study designed to evaluate safety, tolerability, pharmacokinetics (PK), and
pharmacodynamics (PD) of IPI-549 monotherapy and IPI-549 in combination with nivolumab in
subjects with advanced solid tumors.
Approximately 175 subjects will receive IPI-549, either as a monotherapy or in combination
with nivolumab. Subjects will receive IPI-549 until the maximum tolerated dose (MTD) is
achieved or until disease progression or unacceptable toxicity.
Part A (QD dosing) (and Part B (BID dosing) if necessary) a dose escalation part of the study
will evaluate the safety and tolerability, PK, and PD of IPI-549 as a single agent in
subjects with advanced solid tumors. Part A/B will determine the recommended phase 2 dose
(RP2D) for IPI-549 single agent that is going to be administered in Part D as a single agent
and Part C in combination with nivolumab.
Part C a dose-escalation part of the study will evaluate the safety and tolerability, PK, and
PD of IPI-549 when administered in combination with IV nivolumab 240 mg every 2 weeks (Q2W)
in subjects with advanced solid tumors. Part C will determine the RP2D for the combination of
IPI-549 and nivolumab (combination RP2D).
Part D will evaluate the safety, tolerability, PK, PD, and preliminary clinical activity of
IPI-549 administered as a single agent in a cohort of subjects with advanced solid tumors.
Part D, Cycle 2 will also include a pilot food (a high-fat meal) effect evaluation that will
have 8 subjects out of the entire cohort of subjects participating in the Part D.
Part E will evaluate the safety, tolerability, PK, PD, and preliminary clinical activity of
IPI-549 in combination with intravenous (IV) nivolumab 240 mg Q2W in a cohort of subjects
with non-small cell lung cancer (NSCLC), a cohort of subjects with melanoma and a cohort of
subjects with Squamous Cell Cancer of the Head and Neck (SCCHN). One or more cohorts of
subjects with additional tumor types may be enrolled if supported by data generated in dose
escalation or earlier expansion cohorts. To be eligible for enrollment in Part E, subjects
must have received an anti-PD1/PD-L1 as their most recent treatment prior to study entry. The
dose level to be administered in Part E will be the combination RP2D as determined in Part C.
Part F will evaluate the safety, tolerability, PK, PD, and preliminary clinical activity of
IPI-549 in combination with intravenous (IV) nivolumab 240 mg Q2W in a cohort of subjects
with triple negative breast cancer (TNBC). One or more cohorts of subjects with additional
tumor types may be enrolled if supported by data generated in dose escalation or earlier
expansion cohorts. To be eligible for enrollment in Part E, subjects must have no prior
anti-PD1/PD-L1 therapy. The dose level to be administered in Part E will be the combination
RP2D as determined in Part C.
Part G will evaluate the safety, tolerability, PK, PD, and preliminary clinical activity of
IPI-549 in combination with intravenous (IV) nivolumab 240 mg Q2W in a cohort of subjects
with adrenocortical carcinoma (ACC) and a cohort of subjects with mesothelioma who have
received at least first line available therapy. One or more cohorts of subjects with
additional tumor types may be enrolled if supported by data generated in dose escalation or
earlier expansion cohorts. The dose level to be administered in Part E will be the
combination RP2D as determined in Part C.
Part H will evaluate the safety, tolerability, PK, and preliminary clinical activity of
IPI-549 in combination with IV nivolumab 240 mg Q2W in subjects with advanced cancer with
high-circulating MDSCs (ie, ≥ 20.5% as measured by Serametrix CLIA-certified assay); other
indication(s) are to be determined. For subject's with a microsatellite instability-high
tumor, or tumor type for which anti-PD-1/anti-PD-L1 therapy is considered standard of care,
that subject must have previously received an anti-PD-1 or anti-PD-L1 therapy.
Inclusion Criteria:
All subjects must meet the following criteria for inclusion:
- ≥ 18 years of age
- Life expectancy of ≥ 3 months
- Histological or cytological evidence of advanced and/or metastatic carcinoma or
melanoma , excluding sarcoma
- At least 1 measurable disease lesion as defined by RECIST 1.1
- Serum creatinine clearance ≥ 60 mL/min and serum creatinine ≤ 2.0 x the upper limit of
normal (ULN) as determined by either of the following: Estimation as calculated by
Cockcroft-Gault equation or Direct measurement by 24-hour urine collection
- Total bilirubin ≤ 1.5 x ULN (unless elevated due to Gilbert's syndrome)
- Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 2.5 x
ULN (<5x ULN if liver metastasis)
- Adequate hematological function, defined as absolute neutrophil count ≥1.5 x 109/L,
hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100 x 109/L
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (corresponds to
Karnofsky Performance Status (KPS) ≥ 60%)
Subjects entering Part A, B, C, or D must also meet the following additional criterion:
• Failure to respond to standard therapy, or for whom no appropriate therapies are
available (based on the judgement of the Investigator)
Subjects entering Part D, E, F or G must also meet the following additional criterion:
• Willing to undergo 1 pre-treatment and 1 on-treatment tumor biopsy
Subjects entering Part E must also meet the following additional criteria:
- Histological or cytological evidence of NSCLC, melanoma, , human papillomavirus (HPV)
positive or HPV negative SCCHN (oral cavity, pharynx, hypopharynx, larynx,
nasopharyngeal [including undifferentiated nasopharyngeal carcinoma]), or another
tumor type to be determined
- Failure to respond to standard therapy, or for whom no appropriate therapies are
available (based on the judgment of the Investigator The most recent treatment prior
to study entry must be an anti-PD-1 or anti-PD-L1 antibody given as either monotherapy
or in combination
- Subjects with NSCLC Tumors that harbor an actionable genetic alteration for which
there is a corresponding approved therapy for that specific alteration (including but
not limited to alterations in EGFR, ALK, and ROS) must have progressed on, or had
intolerance to, the respective therapy
Subjects entering Part F must also meet the following additional criteria:
- Histological or cytological evidence of estrogen-receptor negative (ER-), progesterone
receptor negative (PgR-) and human epidermal growth factor-2 receptor negative (HER2-)
Breast Cancer by local laboratory testing, based on last available tumor tissue; or
another tumor type to be determined
- ER/PgR negativity to follow local guidelines
- If IHC HER2 2+, a negative FISH test is required
- Inflammatory triple negative breast cancer is allowed
- Must have received and failed/progressed a cytotoxic chemotherapy as first line
therapy per standard of care
- No prior anti-PD-1 or anti-PD-L1 therapy
Subjects entering Part G must also meet the following additional criteria:
- Histological or cytological evidence of ACC, mesothelioma, or another tumor type to be
determined
- Both pleural and peritoneal mesothelioma are allowed
- Epithelioid, sarcomatoid, or biphasic mesothelioma subtypes are allowed
- Progression after at least first line available therapy
Patients entering Part H must also meet the following additional criteria:
High-circulating MDSCs, currently defined for this study as MDSCs
≥ 20.5% as measured by CLIA-certified Serametrix assay Microsatellite status of tumor has
been determined Patients with tumors that are microsatellite instability-high must have
previously received an anti-PD-1/anti-PD-L1 therapy and progressed on therapy If patient's
tumor type is one for which anti-PD-1/anti-PD-L1 therapy is standard of care, patient must
have previously received an anti-PD-1 or anti-PD-L1 therapy and progressed while on that
therapy
Exclusion Criteria:
Subjects are to be excluded from the study if they meet any of the following criteria:
- Severe allergic or anaphylactic reaction to any monoclonal antibody therapy, murine
protein, or known hypersensitivity to any excipient in the study drugs
- Major surgery within 4 weeks prior to Screening
- Subjects who have been treated with chemotherapy, biologic therapy, or other
investigational agent within < 5 times the half-life of the agent or < 28 days
(whichever is shorter) of starting study drug
NOTE: Subjects whose immediate prior treatment was with nivolumab may start study drug 2
weeks after the last dose of nivolumab
- Symptomatic or untreated brain metastases
- Primary central nervous system (CNS) malignancy
- Infection with human immunodeficiency virus (HIV), hepatitis B, or hepatitis C virus
- Ongoing treatment with chronic immunosuppressants (eg, cyclosporine) or systemic
steroids
- Ongoing systemic bacterial, fungal, or viral infections at Screening
NOTE: Subjects on antimicrobial, antifungal, or antiviral prophylaxis are not specifically
excluded if all other inclusion/exclusion criteria are met
- Administration of a live vaccine within 6 weeks of first dose of study drug
- Administration of any of the following within 1 week prior to the administration of
study drug:
- Strong inhibitors or inducers of CYP3A4, including grapefruit products and herbal
supplements
- P-glycoprotein (P-gp) inhibitors
- Warfarin, phenytoin, or other substrates of CYP2C8 or CYP2C9 with a narrow
therapeutic range
- Medications associated with QTc interval prolongation or Torsades de Pointes
- Baseline QT interval corrected with Fridericia's method (QTcF) > 480 ms (average of
triplicate readings) NOTE: criterion does not apply to subjects with a right or left
bundle branch block
- Parts C, D-Annex, and E only: Subjects with active, known, or suspected autoimmune
disease. 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
- Prior surgery or gastrointestinal dysfunction that may affect drug absorption (eg,
gastric bypass surgery, gastrectomy)
- Concurrent active malignancy other than non-melanoma skin cancer, carcinoma in situ of
the cervix, or prostate intraepithelial neoplasia
- Past medical history of interstitial lung disease, drug-induced interstitial lung
disease, radiation pneumonitis which required steroid treatment, or any evidence of
clinically active interstitial lung disease
- History of peptic ulcer and/or gastrointestinal bleed
- History of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia
requiring medication or mechanical control within the last 6 months prior to Screening
- Unstable or severe uncontrolled medical condition (eg, unstable cardiac function,
unstable pulmonary condition including pneumonitis and/or interstitial lung disease,
uncontrolled diabetes) or any important medical illness or abnormal laboratory finding
that would, in the Investigator's judgment, increase the risk to the subject
associated with his or her participation in the study.
