A Phase I Trial of the MET/ALK/ROS1 Inhibitor Crizotinib Combined with the VEGF Inhibitor Pazopanib in Patients with Advanced Solid Malignancies

Figures & data

Table 1 Baseline Demographics and Clinical Characteristics

Characteristics	Total Patients
	N=82
Age (Mean, years)	53
Sex
Male	44 (54%)
Female	38 (46%)
ECOG at Baseline
0	16 (20%)
1	58 (71%)
2	8 (9%)
Prior Treatment
Crizotinib	1
Pazopanib	16
Genomic/IHC testing
Performed	66 (80%)
Not performed	16 (20%)
Tumor Types
Renal	16 (20%)
Ovarian	10 (12%)
Colorectal	7 (8%)
Breast	6 (7%)
Salivary Gland	3 (4%)
Uveal Melanoma	3 (4%)
Thyroid	3 (4%)
Other tumor types**	34(41%)

Notes: **Other tumor types includes (N): cholangiocarcinoma (2), sarcoma (14), hepatocellular carcinoma (2), non-small cell lung cancer (2), urothelial carcinoma (2), adrenocortical carcinoma (1), appendiceal carcinoma (1), squamous cell carcinoma of tonsil (1), granular cell tumor of the foot (1), melanoma (1), mesothelioma (1), gastroesophageal junction cancer (2), nasopharyngeal carcinoma (1), pancreatic cancer (1), pilocytic astrocytoma (1), and squamous cell carcinoma of vulva (1).

Abbreviations: N, number of patients; ECOG, Eastern Cooperative Oncology Group.

Table 2 Crizotinib and Pazopanib Dose-Escalation Schedule (21-Day Cycle), Grade 3/4 Toxicities and Response

Dose Level	Crizotinib, mg PO	Pazopanib, mg PO Daily	Total (N)	Escalation Phase (N)	Expansion Phase (N)	Grade (G) 3/4 Toxicity (N)*	SD≥6 Month or PR/Total Evaluable^#
1	250 QOD	200	4	4	0	Fatigue (2)	0/3
2	200 daily	200	4	4	0	–	1/3
3	200 daily	400	5	5	0	–	1/3
4	250 daily	400	10	7	3	Thrombocytopenia (2), perforation of colon (1)	3/8
5	250 daily	600	9	7	2	Subdural hemorrhage (1), vomiting (1), diarrhea (1), anemia (1), ALT increase (1), AST increase (1), shortness of breath (1)	3/8
6	200 BID	600	33	5	28	Fatigue^Δ (4), fever (1), hematuria (1), diarrhea^Δ (2), hyponatremia^Δ (1), ALT increased (1), ALP increased (1), anemia (1), neutropenia (1), nausea (1), vomiting (1), dizziness (1), abdominal pain^Δ (1)	6/26
7	200 BID	800	9	9	0	Diarrhea^Δ (2), esophagitis (1), fatigue^Δ (2), rash (1), vomiting (1), fatigue (2)	1/5
8	250 BID	800	8	8	0	Dyspnea (1), anorexia (1), fatigue (1), diarrhea (1),	1/5

Notes: *Adverse events deemed at least possibly related to treatment were graded based on the Common Terminology Criteria for Adverse Events, version 4.0 (CTCAEv4.0). ^#Patients were evaluable for response if they had at least one post-baseline scan. ^ΔEvent was defined as a dose-limiting toxicity.

Abbreviations: N, number of patients; QOD, every other day; BID, twice a day; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase.

Figure 1 Waterfall plot depicting best RECISTv1.1 response. Individual patients are represented by vertical bars on the X-axis and best RECISTv1.1 response is depicted as percentage on the Y-axis. Sixty one of 82 patients had at least one post-baseline scan and were evaluable for response. Two patients were marked as progressive disease even though their percentage of tumor increase was less than 20% because of new lesions (*). Dotted lines show 20% increase and 30% decrease in tumor size by RECISTv1.1.

Table 3 Adverse Events at Any Dose Level

Adverse Events		Dosing Level								Total Events
		1	2	3	4	5	6	7	8
		Count	Count	Count	Count	Count	Count	Count	Count
Fatigue	Grade ≤2	1	2	3	6	5	23	6	4	50
	Grade ≥ 3	2	0	0	0	0	4	2	1	9
Nausea	Grade ≤2	0	4	2	8	2	19	6	6	47
	Grade ≥ 3	0	0	0	0	0	1	0	0	1
Diarrhea	Grade ≤2	1	1	2	3	2	15	2	0	26
	Grade ≥ 3	0	0	0	0	1	2	2	1	6
Vomiting	Grade ≤2	0	2	2	2	2	13	1	4	26
	Grade ≥ 3	0	0	0	0	1	1	1	0	3
Anorexia	Grade ≤2	2	0	1	2	1	9	4	6	25
	Grade ≥ 3	0	0	0	0	0	0	0	1	1
ALT increased	Grade ≤2	1	1	2	1	1	9	1	0	16
	Grade ≥ 3	0	0	0	0	1	1	0	0	2
AST increased	Grade ≤2	1	1	2	2	2	11	2	0	21
	Grade ≥ 3	0	0	0	0	1	0	0	0	1
Anemia	Grade ≤2	2	1	0	1	3	6	1	2	16
	Grade ≥ 3	0	0	0	0	1	1	0	0	2
Other AEs	Grade ≤2	5	1	8	7	13	76	21	27	158
	Grade ≥ 3	0	0	0	3	2	7	2	1	15*

Notes: *Other AEs Grade ≥3 (number of patients in parenthesis) includes thrombocytopenia (2), abdominal pain (1), increased alkaline phosphatase (1), dyspnea (1), fever (1), hematuria (1), esophagitis (1), dizziness (1), hyponatremia (1), neutropenia (1), colon perforation (1), rash (1), subdural hemorrhage (1), shortness of breath (1).

Table 4 Stable Disease (SD) ≥6 Months or Partial Response (PR) by RECIST and Characterization by Patient

Cancer Type	Dose Level	Duration of Treatment (Weeks)	Best Response by RECIST 1.0	Number of Prior Therapies	Prior Anti-Angiogeneic Therapy^# (Y/N)	Mutation Analysis
						MET Mut	ROS1 Mut	ALK Mut	Other Alterations**
Ovarian	2	24	0%	5	Y	ND	ND	ND
Ovarian	3	63	−32%	1	N	ND	ND	ND
Renal	4	36	−32%	6	Y	N	N	N	VHL D121Y, KDR C482R, KIT M541L
HNSCC	4	30	0%	3	N	ND	ND	ND
Bladder	4	24	9%	4	Y	ND	ND	ND
Salivary Gland^	5	30	−12%	4	N	Y, cMET N375S	ND	N
Renal	5	24	3%	1	Y	ND	ND	ND
Clear Cell Sarcoma	5	207	−60%	0	N	ND	ND	ND	EWSR1-CREB1 fusion
Colorectal	6	48	−33%	5	Y	N	N	Y, ALK R1209Q	p53 H214FS*33, APC R876*, NTRK3 S165I, RUNX1 S5N
Renal	6	27	−2%	1	N	N	N	N
Myxoid Neoplasm (Sarcoma)	6	123	−32%	0	N	ND	ND	Y, DCTN1-ALK fusion
Colorectal	6	36	18%	5	Y	N	N	N	KRAS G12C, APC R499*
Ovarian	6	27	−2%	3	Y	N	N	N	NSD1 R1019C
Salivary Gland	6	24	−20%	3	N	N	N	N
Granular Cell Tumor	7	27	−31%	1	Y	N	ND	N
Sclerosing Epithelioid Fibrosarcoma	8	78	4%	1	N	N	N	N	EWSR1-CREB3L1 fusion, CDKN2A/B loss

Notes: **Indicates other alterations as detected by fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS). ^#Indicates that none of these patients had received prior ALK or ROS1 inhibitors. ^Indicates the one patient who had received prior MET inhibitor.

Abbreviations: Mut, mutation; ND, not done; N, no mutation; HNSCC, squamous cell carcinoma of the head and neck.