An Open-Label, Dose Escalation, Multicenter Phase I/2 Study of KW-2478 in Combination with Bortezomib in Subjects with Relapsed and/or Refractory Multiple Myeloma
The goal of Phase I of this clinical research study is to find the highest tolerable doses of KW-2478 and bortezomib when given in combination to patients with MM. The goal of Phase II of this clinical research study is to learn if KW-2478 in combination with bortezomib can help to control MM. The safety of this drug combination will be studied in both phases.
Disease Group: Myeloma
Treatment Agent: Bortezomib,KW-2478
Treatment Location: Both at MD Anderson & outside MD Anderson at one or more Collaborating Sites or Institutions
Estimatated Length of Stay in Houston: None
Sponsor: Kyowa Hakko Kirin Pharma, Inc.
Return Visit: 5 visits per cycle.
Home Care: None
The primary objectives will be: To establish the safety, tolerability, and recommended Phase 2 dose (RP2D) of KW-2478 in combination with bortezomib administered intravenously on Days 1, 4, 8, and 11 of a 21-day cycle (Phase 1) To assess the overall response rate (ORR) when subjects with advanced MM are treated with KW-2478 in combination with bortezomib (Phase 2). The secondary objectives will be: To characterize the PK and PD of KW-2478 when administered in combination with bortezomib (Phase 1only) To evaluate for preliminary evidence of efficacy (Phase 1) To determine progression free survival (PFS) and duration of response with KW-2478 in combination with bortezomib (Phase 2).
IRB Review and Approval Date: 09/16/2010
Recruitment Status: Not Accepting
Projected Accrual: 101
1) The subject has MM confirmed by all three of the following
International Myeloma Working Group (IMWG) criteria except as noted:
Clonal bone marrow plasma cells > 10%; or documented plasmacytoma if
clonal bone marrow cells < 10%; Monoclonal paraprotein (M protein) in
either serum or urine (except in subjects with non-secretory myeloma);
Evidence of end-organ damage that can be attributed to the underlying
plasma cell proliferative disorder (to include one of the following):
Hypercalcemia (corrected calcium > 2.75 mmol/L or 11.5 mg/dL); OR
(continued under Inclusion #2)
2) (Continuation of Inclusion #1) Renal insufficiency attributable to myeloma; OR Anemia; normochromic, normocytic with a hemoglobin value > 2 g/dL below the lower limit of normal or a hemoglobin < 10 g/dL; OR Bone lytic lesions, severe osteopenia or pathologic fractures.
3) The subject has received one and no more than three prior regimens for MM to which they did not respond (failed) or from which they have relapsed. A planned treatment of induction regimens followed by autologous stem cell transplant (ASCT) followed by maintenance therapy is considered one regimen. Failure of therapy is defined as either: Failure to achieve at least a PR (IMWG criteria) after a period of therapy of adequate duration, in the Investigator’s opinion, to see such a response; OR Discontinuation of therapy due to toxicity, regardless of response status; (continued under Inclusion #4)
4) (Continuation of Inclusion #3) Development of PD after initial response (complete or partial) to a therapy but PD occurred while continuing to receive that therapy. Relapse is defined as PD (IMWG criteria) after a response to treatment and discontinuation of that treatment.
5) The subject must have disease that can be evaluated by serum or urine levels of M protein or serum free light chains (FLC) if no measurable M protein, as follows: Serum M protein >/= 1 gm/dL; or Urine M protein >/= 200 mg/24hr; or Serum FLC: Involved FLC level >/= 10 mg/dL with abnormal k/alpha FLC ration (normal ration =0.26 - 1.65) in patients without measurable M protein in serum or urine.
6) The subject has an Eastern Cooperative Oncology Group (ECOG) performance status score of </= 2 at study entry.
7) The subject is >/= 18 years of age.
8) The subject has a life expectancy >/= 3 months.
9) The subject has completed any prior chemotherapy (including dexamethasone > 2.5 mg/day) investigational agents, and/or prior radiotherapy at least four weeks prior to entry (nitrosoureas at least six weeks), and monoclonal antibody therapy at least six weeks prior to the first dose of study medication.
10) If a subject has received prior treatment with thalidomide, lenalidomide or high dose steroids, these medications must be stopped at least four weeks prior to the first dose of study medication.
11) If the subject has received prior bortezomib (or another proteasome inhibitor) alone or in combination, then they must not have progressed while receiving bortezomib (or another proteasome inhibitor) and a minimum of 60 days must have elapsed since their last treatment with bortezomib (or another proteasome inhibitor).
12) The subject has resolution of all clinically significant toxic effects of prior cancer therapy to Grade </= 1 by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE v 4.0), excluding the Inclusion Criteria required in #13,14, and 15 below.
13) The subject has adequate hematological function: absolute neutrophil count (ANC) >/= 1,000 cells/microL (or >/= 1 x 10^9/L); hemoglobin >/= 9.0 g/dL (may be transfused to meet this requirement); and platelets >/= 50,000 cells/microL (or >/= 50 x 10^9/L).
14) The subject has adequate hepatic function: bilirubin < 1.5 times the upper limit of normal ([ULN], excluding unconjugated hyperbilirubinemia in Gilbert’s syndrome), aspartate transaminase (AST), and alanine transaminase (ALT) each < 2.5 x ULN
15) The subject has serum creatinine </= 177 micromol/L (2.0 mg/dL) or a calculated creatinine clearance > 30 mL/min/1.73 m^2 for subjects with creatinine levels > 177 micromol/L.
16) The subject has provided signed informed consent. Written informed consent must be obtained prior to performing any study-related procedures.
17) For women of child-bearing potential (WOCBP) a negative pregnancy test must be obtained prior to study entry. WOCBP and male subjects with female partners of child-bearing potential must, during study drug treatment, and for 3 months after last bortezomib administration, agree to use a highly effective method of birth control (i.e., condom or diaphragm + spermicide, some intrauterine devices, hormonal contraceptive, true sexual abstinence or male vasectomy). (Continued under Inclusion # 18).
18) (Conintuation of Inclusion # 17) Since it is not known whether the treatment reduces the effectiveness of hormonal contraception a second non-hormonal method should always be added to a hormonal method. Women are considered not to be of child-bearing potential if they have been surgically sterilized (hysterectomy, tubal occlusion or bilateral salpingectomy) or are postmenopausal (complete absence of menses for two consecutive years and a serum FSH level of >/= 30 IU/L in the absence of hormone replacement therapy [HRT]).
19) The subject has completed all assessments for determining eligibility within 21 days preceding the first dose of KW-2478/bortezomib.
1) The subject has a significant uncontrolled inter-current illness
including, but not limited to: ongoing or active infection requiring
parenteral antibiotics; clinically significant cardiac disease (class
III or IV of the New York Heart Association classification); unstable
angina pectoris, myocardial infarction within 6 months, or is post
angioplasty or stenting within 6 weeks; uncontrolled hypertension (i.e.
systolic blood pressure > 160 mm Hg, diastolic BP > 100 mmHg),
found on two consecutive measurements separated by a 1-week period;
(Continued under Exclusion #2)
2) (Continuation of Exclusion #1) clinically significant cardiac arrhythmia; uncontrolled diabetes; history of macular degeneration or blindness in one eye or any other ocular diagnosis where the benefit - risk ratio would favor exclusion from the trial; or intracranial disease or epidural disease.
3) The subject has non-secretory MM or bi-clonal MM.
4) The subject has a known hypersensitivity to boron or mannitol.
5) The subject has received prior treatment with any Hsp90 inhibitors (including KW-2478).
6) The subject is taking corticosteroids at a dose equivalent to > 10 mg prednisone daily.
7) The subject is having corticosteroid treatment in the acceptable dose range that has been changed in the two weeks prior to study entry.
8) The subject has > Grade 1 sensory and/or motor neuropathy.
9) The subject has known human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness.
10) The subject has known hepatitis B or C or other active liver disease.
11) The subject is pregnant (confirmed by beta-human chorionic gonadotrophin [Beta-HCG]) or lactating/breastfeeding.
12) The subject is taking immunosuppressive therapy other than low-moderate dose corticosteroids, as described above (see Exclusion Criteria #6 and 7 above).
13) The subject is receiving any concomitant medication known to commonly cause QTc interval prolongation.
14) The subject has a psychiatric illness, disability or social situation that would compromise the subject’s safety, ability to provide consent, or limit his or her compliance with study requirements.
15) The subject had major surgery within six weeks prior to screening.
16) The subject has received an allograft transplant. Autografts are allowed.
17) The subject has received radiotherapy except for local treatment for palliation within the four weeks prior to the first dose of KW-2478, or has lack of recovery from any radiotherapy-related acute toxicity.
18) The subject has other malignant conditions and has not been disease-free for > 5 years, except for adequately treated basal or squamous cell carcinoma of the skin and cervical carcinoma in situ.
19) The subject has a known current recreational drug use, drug dependence, or alcohol abuse.
20) The subject is judged by the Investigator to be inappropriate for study participation for any reason, including an inability to communicate or cooperate with study personnel.
21) The subject requires potent inhibitors/inducers of CYP3A4 (e.g. ketoconazole, ritonavir) or of cytochrome P450 isoenzyme 2C19 ([CYP2C19] e.g. moclobemide, rifampicin, fluvoxamine). Certain food substances (e.g. grapefruit, grapefruit juice, and green tea) are also prohibited after the subject signs the informed consent form (ICF) to enroll in this study. In addition, Concomitant inhibitors/substrates of P-glycoprotein should be used with caution.
22) The subject has clinically significant findings on the screening slit lamp retinal examination (Phase 1 only); or has experienced any change in visual acuity or other ocular symptoms at screening or prior to the first dose (Phase I and Phase 2).