Phase 1 trial of ibrutinib and carfilzomib combination therapy for relapsed or relapsed and refractory multiple myeloma

Figures & data

Table 1. Cohort descriptions (N = 43).

Treatment	Cohort 1(n = 3)	Cohort 2a(n = 5)	Cohort 2b(n = 17)	Cohort 3b(n = 18)
Ibrutinib	560 mg	560 mg	560 mg	840 mg
Carfilzomib	27 mg/m^2	36 mg/m^2	36 mg/m^2	36 mg/m^2
Dexamethasone	–	–	+	+

Cohort 3a not opened based on PCYC-1111 outcomes noted with the inclusion of dexamethasone to study treatment [8].

Table 2. Baseline characteristics.

Characteristic	Cohort 1 (n = 3)	Cohort 2a (n = 5)	Cohort 2b (n = 17)	Cohort 3b (n = 18)	Total (N = 43)
Median age, years (range)	69 (68–71)	72 (60–82)	60 (47–83)	59 (44–76)	63 (44–83)
Median time from diagnosis, years (range)	8.2 (1.7–18.6)	4.2 (2.0–12.5)	5.0 (2.1–25.3)	4.0 (0.5–9.7)	4.2 (0.5–25.3)
Male, %	67	80	35	50	49
ECOG performance status, %
0	33	20	24	33	28
1	67	80	71	50	63
2	0	0	6	17	9
Chromosomal abnormalities by FISH, %
t(11;14)	33	20	6	6	9
t(4;14)	0	20	12	28	19
del17p	0	0	6	11	7
High-risk cytogenetics^a	0	20	18	33	23
ISS stage at baseline, n
I	3	1	10	8	22
II	0	2	3	6	11
III	0	2	3^b	3^b	8
Median prior lines of therapy, n (range)	3 (2–9)	3 (2–7)	3 (2–5)	2.5 (2–7)	3 (2–9)
Disease status to last treatment, %
Relapsed	0	40	12	6	12
Refractory	100	60	88	94	88
Autologous stem cell transplant, %	100	60	76	61	70
Alkylator, %	100	100	76	94	88
IMiD,^c %
Thalidomide	0	40	29	22	26
Thalidomide refractory	0	20	0	11	7
Lenalidomide	100	100	94	100	98
Lenalidomide refractory	100	60	71	72	72
Pomalidomide	33	20	41	22	30
Pomalidomide refractory	33	20	35	22	28
PI,^c %
Bortezomib	100	100	100	100	100
Bortezomib refractory	67	60	76	78	74
Carfilzomib	0	0	6	17	9
Carfilzomib refractory	0	0	0	0	0

ECOG: Eastern Cooperative Oncology Group; FISH: fluorescence in situ hybridization; IMiD: immunomodulatory drug; PI: proteasome inhibitor.

^at(4;14) and/or del17p.

^bData not available for two patients at baseline.

^cReceived in last line of therapy: no PI or IMiD (n = 3); PI and IMiD (n = 12); PI or IMiD (n = 28).

Table 3. Adverse events (> 15% and/or grade ≥ 3 in ≥ 3 patients).

	Cohort 1 (n = 3)		Cohort 2a (n = 5)		Cohort 2b (n = 17)		Cohort 3b (n = 18)		Total (N = 43)
Adverse event, %	All	Grade ≥3	All	Grade ≥3	All	Grade ≥3	All	Grade ≥3	All	Grade ≥3
Fatigue	0	0	80	40	65	18	44	11	53	16
Diarrhea	0	0	60	20	65	24	39	6	49	14
Cough	33	0	40	0	41	0	56	0	47	0
Constipation	33	0	60	0	35	0	44	0	42	0
Nausea	0	0	0	0	41	6	50	0	37	2
Anemia	33	33	60	40	35	24	28	6	35	19
Pyrexia	33	0	60	0	41	24	17	0	33	9
Upper respiratory tract infection	33	0	0	0	41	12	33	0	33	5
Dyspnea	0	0	60	20	35	6	22	6	30	7
Headache	33	0	40	0	47	6	11	0	30	2
Hypertension	33	33	40	40	35	29	22	11	30	23
Insomnia	0	0	0	0	41	0	33	0	30	0
Epistaxis	0	0	60	0	29	0	22	0	28	0
Hypokalemia	0	0	40	0	41	12	17	6	28	7
Thrombocytopenia	33	33	20	0	18	6	39	17	28	12
Urinary tract infection	0	0	20	0	29	12	28	6	26	7
Arthralgia	0	0	60	0	24	0	11	0	21	0
Peripheral edema	0	0	20	0	18	0	28	0	21	0
Abdominal pain	0	0	20	0	24	0	17	0	19	0
Acute kidney injury	33	0	20	0	24	12	56	6	19	7
Muscle spasms	0	0	20	0	18	0	22	0	19	0
Pneumonia	33	33	40	40	12	12	17	17	19	19
Rash maculo-papular	0	0	0	0	24	18	17	0	16	7
Vomiting	0	0	20	0	24	12	11	0	16	5
Back pain	0	0	0	0	24	12	11	6	14	7
Hyperglycemia	0	0	0	0	18	12	17	11	14	9
Neutropenia	0	0	20	20	12	6	6	6	9	7
Sepsis	0	0	0	0	18	18	0	0	7	7

Table 4. Best response by IMWG response criteria.

Treatment, %	Cohort 1 (n = 3)	Cohort 2a (n = 5)	Cohort 2b (n = 17)	Cohort 3b^a (n = 17)	Total (N = 42)
sCR/CR	0	0	0	6	2
VGPR	0	0	29	24	21
PR	67	40	41	41	43
MR	0	0	12	12	10
ORR (≥PR)	67	40	71	71	67
CBR (≥MR)	67	40	82	82	76

CBR defined as ≥ MR by International Myeloma Working Group criteria.

CBR: clinical benefit rate; CR: complete response; MR: minimal response; ORR: overall response rate; PR: partial response; sCR: stringent complete response; VGPR: very good partial response.

^aOne patient not evaluable for response because of early discontinuation.

Figure 1. PFS in specific subgroups. PFS by refractory status and overall (A). PFS in patients with high-risk cytogenetics [t(4;14); del17p] (B). PFS: progression-free survival; PI: proteasome inhibitor; IMiD: immunomodulatory drug.

Figure 2. Pharmacokinetics of ibrutinib in patients with multiple myeloma. Mean steady-state ibrutinib plasma concentration–time profiles in the current study (PCYC-1119) and PCYC-1111 (A). Steady-state ibrutinib area under the curve (AUC; with background carfilzomib), with and without dexamethasone in the current study cohorts and PCYC-1111 (B). ^aPCYC-1111 was a phase 1/2, open-label, nonrandomized, multicenter study of ibrutinib with or without dexamethasone in relapsed or relapsed and refractory multiple myeloma; dexamethasone dose was 4 mg weekly [8].

Richardson PG, Bensinger WI, Huff CA, et al. Ibrutinib in combination with low-dose dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: results from a multicenter phase 2 trial. Clin Lymphoma Myeloma Leuk. 2015;15:e80–e81.

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