A Phase 1/2 Proof-of-concept study of the combination of ACP-196 and ACP-319 in subjects with B-cell malignancies
The main purpose of the study is to test the safety of ACP-196 and ACP-319, now known as study drugs, as different dose levels. We want to find out what effects, good and/or bad, it has on you and your B-cell malignancies, who have relapsed or failed to respond to their anticancer therapy.
Genes are the units of DNA--the chemical structure carrying genetic information--that determine many human characteristics such as the color of your eyes, your height, and whether you are male or female.
Certain genes in cancer cells may determine how the tumor grows or spreads and how it may respond to different drugs. Part of this study will be to test those genes in your cancer cells. This testing is not optional. Another purpose of this study is to test your genetic makeup using your blood or tissue samples [explain if it's optional/mandatory]. This will be explained in more detail in the WHY AM I BEING ASKED TO PARTICIPATE IN GENETIC TESTING section of the study consent form
B-cell malignancies, which include non-GCB DLBCL, MCL, FL, WM, CLL/SLL, MM, B-ALL, and Richter's syndrome.
1) Diagnosis of non-GCB DLBCL, MCL, or iNHL as documented by medical records
and with histology based on criteria established by the WHO.
a) If the subject has DLBCL, it is characterized as de novo non-GCB DLBCL
(Choi 2009 or Hans 2004). Note: PMBCL is excluded from this protocol.
b) If the subject has MCL, it is characterized by documentation of monoclonal
B-cells that have a chromosome translocation t(11;14)(q13;q32) and/or
overexpress cyclin D1.
c) If the subject has iNHL, the histology shows 1 of the following subtypes:
i) FL Grade 1, 2, or 3a
2) Prior treatment for lymphoid malignancy:
a) If the subject has DLBCL, there is no curative option with conventional therapy
and the prior treatment included >= 1 prior combination chemoimmunotherapy
regimen (eg, anthracycline based therapy with rituximab).
b) If the subject has MCL or iNHL, the prior treatment comprised any of the
i) 1 regimen containing an anti-CD20 antibody administered for >= 2 doses
ii) >= 1 regimen containing 1 cytotoxic agent (eg, bendamustine,
chlorambucil, cyclophosphamide, cytarabine, doxorubicin) administered for 2 cycles, and/or
iii) >= 1 regimen containing yttrium90-ibritumomab tiuxetan (Zevalin) or
3) Presence of radiographically measurable lymphadenopathy or extranodal
lymphoid malignancy (defined as the presence of a >= 2.0 lesion as measured in
the longest dimension by CT scan). Note: Not applicable to subjects with WM and
4) ANC >= 1.5 x 109/L or platelet count >= 100 x 109/L unless due to disease
involvement in the bone marrow.
5) Men and women >= 18 years of age.
6) Documented active disease.
7) ECOG performance status of <= 2.
8) Agreement to use acceptable forms of contraception during the study and for 90 days after the last dose of study drugs if sexually active and able to bear or
9) Agreement to refrain from sperm donation during the study and for 90 days after
the last dose of study drugs.
10) Willing and able to participate in all required evaluations and procedures in this
study protocol including swallowing capsules without difficulty.
11) Ability to understand the purpose and risks of the study and provide signed and
dated informed consent and authorization to use protected health information (in
accordance with national and local subject privacy regulations).
Part 2 Additional disease entry criteria:
12) DLBCL (GCB): Confirmed diagnosis of DLBCL with disease characterized as
GCB subtype by immunohistochemistry (Choi 2009 or Hans 2004) and meeting
the rest of the criteria as defined above.
13) Richter's syndrome: Confirmed diagnosis of previously treated CLL/SLL with
previously untreated and biopsy-proven DLBCL due to Richter transformation and
meeting the rest of the criteria as defined above.
14) MM: Confirmed diagnosis of MM, which has relapsed after, or been refractory to
>= 1 prior therapy for MM, and is progressing at the time of study entry and meeting
the rest of the criteria as defined above.
15) B-ALL: Confirmed diagnosis of previously treated B-ALL and meeting the rest of
the criteria as defined above.
3.3.2 Exclusion Criteria
Subjects will be ineligible for this study if they meet any of the following criteria:
1) Prior malignancy, except for adequately treated basal cell or squamous cell skin
cancer, in situ cervical cancer, or other cancer from which the subject has been
disease free for >= 2 years or which will not limit survival to < 2 years. Note: these
cases must be discussed with the Acerta Pharma Medical Monitor.
2) A life-threatening illness, medical condition or organ system dysfunction which, in
the investigator's opinion, could compromise the subject's safety, interfere with the
absorption or metabolism of ACP-196 and/or ACP-319, or put the study outcomes
at undue risk.
3) Significant cardiovascular disease such as uncontrolled or symptomatic
arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart
Association Functional Classification, or LVEF < 40%.
4) Malabsorption syndrome, disease significantly affecting gastrointestinal function,
or resection of the stomach or small bowel, symptomatic inflammatory bowel
disease, partial or complete bowel obstruction, or gastric restrictions and bariatric
surgery such as gastric bypass.
5) CNS involvement by lymphoma/leukemia.
6) Any therapeutic antibody within 4 weeks of first dose of study drug.
7) The time from the last dose of the most recent chemotherapy or experimental
therapy to the first dose of study drug is < 5 times the half-life of the previously
8) Any prior irreversible Btk or PI3K(d) inhibitor therapy. Note: Prior treatment with
reversible, noncovalent Btk inhibitors is not excluded on this protocol.
9) Ongoing immunosuppressive therapy, including systemic or enteric corticosteroids
for treatment of lymphoid cancer or other conditions. Note: Subjects may use
topical or inhaled corticosteroids or low-dose steroids (<= 10 mg of prednisone or
equivalent per day) as therapy for comorbid conditions. During study participation,
subjects may also receive systemic or enteric corticosteroids as needed for
treatment-emergent comorbid conditions.
10) Use of a potent inhibitor or inducer of CYP3A4/3A5 (see Appendix 3) within
7 days before dose of study drug or expected requirement for use of a
CYP3A4/3A5 inhibitor or inducer during the first 28 days of administration of study
11) Use of a potent inhibitor or inducer of drug transporters or conjugating enzymes
(see Appendix 3) within 7 days before first dose of study drug or expected
requirement for use of such an inhibitor or inducer during the first 28 days of
administration of study drugs.
12) Known history of HIV or active infection with HCV or HBV or any uncontrolled
active systemic infection.
13) Major surgery within 4 weeks before first dose of study drugs.
14) History of stroke or intracranial hemorrhage within 6 months before the first dose
of study drugs.
15) Ongoing, drug-induced liver injury, alcoholic liver disease, non-alcoholic
steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused
by cholelithiasis, cirrhosis of the liver, or portal hypertension.
16) History of or ongoing drug-induced pneumonitis.
17) ANC < 0.5 x 109/L or platelet count < 50 x 109/L unless due to disease
involvement in the bone marrow.
18) Creatinine > 1.5 x institutional ULN; total bilirubin > 1.5 x ULN (unless due to
Gilbert's disease); and AST or ALT > 3.0 x ULN.
19) Significant screening ECG abnormalities including left bundle-branch block,
2nd degree AV block type II, 3rd-degree AV block, Grade >= 2 bradycardia, and
QTc > 480 msec.
20) Breastfeeding or pregnant.
21) Concurrent participation in another therapeutic clinical trial.
18 - 99
Healthy Volunteers Needed
Duration of Participation
Until participant's cancer can no longer be detected.
Knight Clinical Trials information Line