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A Phase 1 Study of AV-299 (Formerly SCH 900105) Administered by IV Infusion as Monotherapy in Advanced Solid Tumors, Lymphomas, or Multiple Myeloma or in Combination With Erlotinib in Advanced Solid Tumors


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Malignant Solid Tumor, Lymphomas, Multiple Myeloma

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Trial Information

A Phase 1 Study of AV-299 (Formerly SCH 900105) Administered by IV Infusion as Monotherapy in Advanced Solid Tumors, Lymphomas, or Multiple Myeloma or in Combination With Erlotinib in Advanced Solid Tumors


Inclusion Criteria:



- Diagnosis of an advanced solid tumor malignancy or lymphoma (non-Hodgkin's or
Hodgkin's lymphoma).

- Histological or cytological evidence of malignancy.

- Advanced malignancy, metastatic or unresectable, that has recurred or progressed
following standard therapy or failed standard therapy; or for which no standard
therapy currently exists, or for which subject is not a candidate for, or is
unwilling to undergo, standard therapy.

- Disease that is currently not amenable to curative surgical intervention.

- ECOG performance status of 0-1. Subjects with performance status of 2 will be
considered only after discussion between the investigator and medical monitor.

- 18 years or older, of either sex, and of any race.

- Subject (and/or parent/guardian for subject who otherwise is unable to provide
independent consent, if acceptable to and approved by the site and/or site's IRB)
must be willing to give written informed consent and be able to adhere to dose and
visit schedules.

- Female subjects of childbearing potential must have negative pregnancy test within 5
days prior to first dose of study drug.

- Female subjects of childbearing potential and male subjects whose sexual partners are
of childbearing potential must agree to abstain from sexual intercourse or to use an
effective method of contraception during the study and for 60 days after the last
dose of AV-299 (formerly SCH 900105). Examples of effective methods of contraception
include, but are not limited to, oral contraceptives or double barrier methods such
as condom plus spermicide or condom plus diaphragm.

- Adequate hematologic function as evidenced by Hg ≥ 9g/dL, WBC ≥ 3000 per mm3, ANC ≥
1500 per mm3 and platelet count ≥ 100,000 per mm3.

- Adequate hepatic function as evidenced by a serum bilirubin level ≤1.5 × ULN (except
with known Gilbert's Syndrome) and

- For subjects in the dose-escalation cohorts and the Phase 1b evaluation of AV-299
(formerly SCH 900105) in combination with erlotinib:

-- Serum AST/ALT levels ≤3 × ULN for the reference laboratory

- For subjects in the RP2D safety expansion cohort:

- Without known hepatic metastasis serum AST/ALT levels ≤3 × ULN for the reference
laboratory

- With known hepatic metastasis serum AST/ALT levels ≤5 × ULN.

- Adequate renal function as evidenced by a serum creatinine level ≤ 1.5 × ULN or
a calculated creatinine clearance > 60 mL/min.

- Adequate coagulation function as evidenced by PTT ≤ 1.5 × ULN and INR ≤ 1.5 ×
ULN

- Recovery from the effects of any prior surgery, radiotherapy, or systemic
antineoplastic therapy.

- Subjects with abnormal liver function tests (LFTs) who have not been screened
for Hepatitis B or C within the past 6 months prior to study enrollment, will
need to be screened for Hepatitis B and C and can only be enrolled if the
screening is negative.

Diagnosis and Main Criteria for Inclusion for the Multiple Myeloma Exploratory Cohort
Subjects to be Included

- Diagnosis of symptomatic relapsed or refractory multiple myeloma. Note: For relapsed
disease, subject must have PD after having achieved at least stable disease for ≥ 1
cycle of treatment to ≥ 1 prior regimen. For refractory disease, subject must have
documented evidence of PD during or within 60 days (measured from the end of the last
cycle) of completing treatment with the last anti-myeloma drug regimen used just
prior to study entry.

- Measurable disease assessed by one of the following:

- Serum monoclonal protein ≥ 1.0 g/dL by protein electrophoresis;

- > 200 mg of monoclonal protein in the urine on 24 hour electrophoresis;

- Serum immunoglobulin free light chain ≥ 10 mg/dL AND abnormal serum
immunoglobulin kappa to lambda free light chain ratio; or,

- Monoclonal bone marrow plasmacytosis ≥ 30% (evaluable disease). Note: All above
evaluations, for which there are measurable results at screening, will be
repeated as indicated in the visit schedule and the schedule of assessments,
with the exception of bone marrow plasmacytosis. Bone marrow plasmacytosis will
be repeated for disease/response assessment according to the visit schedule and
the schedule of assessments if it is the only measurable result at screening.
If both serum and urine M-proteins are present, both must be followed in order
to evaluate response.

- At least 2 prior therapies

- ECOG performance status of 0, 1, or 2.

- 18 years or older, of either sex, and of any race.

- Subject (and/or parent/guardian for subject who otherwise is unable to provide
independent consent, if acceptable to and approved by the site and/or site's IRB)
must be willing to give written informed consent and be able to adhere to dose and
visit schedules.

- Female subjects of childbearing potential must have negative pregnancy test within 5
days prior to first dose of study drug.

- Female subjects of childbearing potential and male subjects whose sexual partners are
of childbearing potential must agree to abstain from sexual intercourse or to use an
effective method of contraception during the study and for 60 days after the last
dose of AV-299 (formerly SCH 900105). Examples of effective methods of contraception
include, but are not limited to, oral contraceptives or double barrier methods such
as condom plus spermicide or condom plus diaphragm.

- Adequate hematologic function as evidenced by Hg ≥ 9g/dL, ANC ≥ 1000 per mm3, and
platelet count ≥ 50,000 per mm3. Screening platelet count should be independent of
platelet transfusions for ≥ 2 weeks.

- Adequate hepatic function as evidenced by a serum bilirubin level ≤ 1.5 × ULN (except
with known Gilbert's Syndrome) and serum AST and ALT levels ≤ 3 × ULN.

- Adequate renal function as evidenced by a serum creatinine level ≤ 3.0 mg/dL.

- Adequate coagulation function as evidenced by PTT ≤ 1.5 × ULN and INR ≤ 1.5 × ULN.

- All previous cancer chemotherapy, including radiation, hormonal therapy, and surgery,
must have been discontinued ≥ 2 weeks prior to first dose of study drug.

- Subjects with abnormal liver function tests (LFTs) who have not been screened for
Hepatitis B or C within the past 6 months prior to study enrollment, will need to be
screened for Hepatitis B and C and can only be enrolled if the screening is negative.

- Subject willing to provide blood and if feasible, bone marrow samples for research
purposes.

Exclusion Criteria:

- Women who are breast-feeding, pregnant, or intend to become pregnant.

- Subjects with primary CNS malignancy or symptomatic CNS metastases, with the
exception that subjects with glioblastoma multiforme may be enrolled in the RP2D
Safety Expansion Cohort and in the Phase 1b evaluation of AV-299 (formerly SCH
900105) in combination with erlotinib. Subjects with treated brain metastases that
have remained stable for at least 3 months without steroids are allowed. Subjects
with signs or symptoms or history of brain metastasis must have a CT or MRI scan of
the brain within 1 month prior to the first dose of study drug. Subjects with spinal
cord or nerve root compression who have completed treatment at least 4 weeks prior to
the first dose of study drug and are stable without steroid treatment for at least 1
week prior to the first dose of study drug are allowed. Subjects with leptomeningeal
metastases are not allowed.

- Hematologic malignancies other than lymphoma

- Any of the following within 6 months prior to administration of study drug:

Myocardial infarction (MI), severe /unstable angina pectoris, coronary/peripheral artery
bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient
ischemic attack or seizure disorder.

- Serious and/or symptomatic active infection within 14 days prior to first dose of
study drug. Subjects who have asymptomatic or mild infection and taking a short
course of antibiotics (ie, UTI, bronchitis) may be allowed after discussion with the
medical monitor.

- Baseline QTc interval as follows per Bazett's formula: Females > 470 msec; Males >
450 msec.

- Persistent, unresolved CTCAE v3.0 Grade 2 or higher drug-related toxicity (except
alopecia, erectile dysfunction, hot flashes, and decreased libido) associated with
previous treatment.

- Inadequate recovery from any prior surgical procedure or major surgical procedure
performed within 4 weeks prior to administration of first dose or major surgery
within 3 weeks prior to first dose of study drug.

- Any other medical or psychiatric condition that, in the opinion of the investigator,
might interfere with the subject's participation in the trial or interfere with the
interpretation of trial results.

- Known Human Immunodeficiency Virus (HIV) infection or a known HIV-related malignancy.

- Known active hepatitis B or C.

- Known hypersensitivity to any of the components of AV-299 (formerly SCH 900105).

- Radiotherapy within 3 weeks prior to first study drug administration.

- Inability to comply with the protocol requirements or participation in any other
clinical study.

- Any medications listed in the table on "Prohibited Medications".

- Active alcohol abuse.

- Stem cell/bone marrow transplant within 6 months of first dose of study drug.

Additional Exclusion Criteria for Subjects Enrolled in the Phase 1b Evaluation of AV-299
(formerly SCH 900105) in Combination with Erlotinib:

- Inability to take oral medications

- Grade 2 or higher diarrhea at baseline, or inflammatory bowel disease

- Any gastrointestinal disorder that may interfere with the absorption of oral
medications

- Acute onset of new or progressive pulmonary symptoms, such as dyspnea, cough or fever
within 4 weeks prior to first study treatment, or diagnosis of interstitial lung
disease (ILD)

Exclusion for the Multiple Myeloma Exploratory Cohort

- Women who are breast-feeding, pregnant, or intend to become pregnant.

- Active malignancy of any kind requiring or likely to require treatment within the
next 12 months, with the exception of basal cell skin cancer, in situ cervical
cancer, in situ breast cancer and asymptomatic prostate cancer.

- Any of the following prior to first dose of study drug: POEMS (polyneuropathy,
organomegaly, endocrinopathy, monoclonal protein, and skin changes), plasma cell
leukemia, Waldenstrom's macroglobulinemia.

- Any of the following within 6 months prior to administration of study drug:

Myocardial infarction (MI), severe /unstable angina pectoris, coronary/peripheral artery
bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient
ischemic attack or seizure disorder.

- Serious and/or symptomatic active infection within 14 days prior to first dose of
study drug. Subjects who have asymptomatic or mild infection and taking a short
course of antibiotics (ie, UTI, bronchitis) may be allowed after discussion with the
medical monitor.

- Baseline QTc interval as follows per Bazett's formula: Females > 470 msec; Males >
450 msec.

- Persistent, unresolved CTCAE v3.0 Grade 2 or higher drug-related toxicity (except
alopecia, erectile dysfunction, hot flashes, and decreased libido) associated with
previous treatment.

- Inadequate recovery from any prior surgical procedure or major surgical procedure
performed within 4 weeks prior to administration of first dose or major surgery
within 3 weeks prior to first dose of study drug.

- Any other medical or psychiatric condition that, in the opinion of the investigator,
might interfere with the subject's participation in the trial or interfere with the
interpretation of trial results.

- Known Human Immunodeficiency Virus (HIV) infection or a known HIV-related malignancy.

- Known active hepatitis B or C.

- Known hypersensitivity to any of the components of AV-299 (formerly SCH 900105).

- Radiotherapy within 3 weeks prior to first study drug administration, except when
used as palliative treatment for pain control.

- Inability to comply with the protocol requirements or participation in any other
clinical study.

- Any medications listed in the table on "Prohibited Medications".

- Active alcohol abuse.

- Maintenance steroid therapies of > 20 mg/day prednisone, > 4 mg/day dexamethasone, >
80 mg/day hydrocortisone, or equivalent.

NOTE: Maintenance steroid therapies of ≤ 20 mg/day prednisone, ≤ 4 mg/day dexamethasone, ≤
80 mg/day hydrocortisone, or equivalent are allowed provided that the subject is on a
stable dose for at least 2 weeks prior to first dose of study drug or the dose has not
been adjusted upwards in the 2 weeks prior to first dose of study drug.

- Prior therapy involving anti-HGF antibody or c-Met small molecule inhibitor.

- Allogeneic stem cell/bone marrow transplant within 12 months of first dose of study
drug.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Dose Limiting Toxicity and Recommended Phase 2 dose

Outcome Description:

Assessment of any dose-limiting toxicity

Outcome Time Frame:

Following 4 weeks of treatment

Safety Issue:

Yes

Principal Investigator

Philip Komarnitsky, MD

Investigator Role:

Study Director

Investigator Affiliation:

AVEO Pharmaceuticals, Inc.

Authority:

United States: Food and Drug Administration

Study ID:

P05538

NCT ID:

NCT00725634

Start Date:

September 2008

Completion Date:

December 2013

Related Keywords:

  • Malignant Solid Tumor
  • Lymphomas
  • Multiple Myeloma
  • Neoplasms,
  • Lymphoma,
  • Multiple Myeloma,
  • Neoplasms, Plasma Cell,
  • Neoplasms by Histologic Type,
  • Lymphoproliferative Disorders,
  • Lymphatic Diseases, Immunoproliferative Disorders
  • Immune System Diseases Hemostatic Disorders
  • Vascular Diseases
  • Cardiovascular Diseases
  • Paraproteinemias
  • Blood Protein Disorders
  • Hematologic Diseases
  • Hemorrhagic Disorders
  • Erlotinib
  • Protein Kinase Inhibitors
  • Enzyme Inhibitors,
  • Molecular Mechanisms of Pharmacological Action
  • Pharmacologic Actions
  • Lymphoma
  • Multiple Myeloma
  • Neoplasms, Plasma Cell
  • Neoplasms

Name

Location

Investigational Site 2Scottsdale, Arizona  
Investigational Site 3Columbus, Ohio  
Investigational Site 1San Antonio, Texas