A Phase Ib Study of Single‐Agent Idelalisib Followed by Idelalisib in Combination with Chemotherapy in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

Abstract

Lessons Learned

• Although this study of idelalisib in patients with PDAC was limited in size and duration because of early termination, idelalisib exposure resulted in an overall safety profile consistent with studies in hematological malignancies, except that the incidences of diarrhea and colitis were reduced in patients with PDAC.

• Preclinical studies of the PI3K pathway in PDAC and positive clinical results of PI3K inhibition in other cancers support the continued development of PI3K inhibitors in PDAC.

Background

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal solid tumors and is often refractory to treatment. Phosphatidylinositol‐3 kinase (PI3K) δ inhibition influences regulatory immune cell function and improves survival in preclinical PDAC models. Here, idelalisib, an inhibitor of PI3Kδ, was investigated as treatment for metastatic PDAC.

Methods

This was an open‐label, multicenter, phase Ib, nonrandomized, dose‐escalation study. Study aims were to investigate the maximum tolerated dose, safety, pharmacokinetics/pharmacodynamics, and efficacy of idelalisib alone and in combination with chemotherapeutics—nab‐paclitaxel and modified (m)FOLFOX6.

Results

Because of early termination, only 16 patients were enrolled in the single‐agent idelalisib arm, 12 of whom received at least one dose of idelalisib. The most common treatment‐emergent adverse events (≥25%) related to idelalisib (n = 12) were increased aspartate aminotransferase, pyrexia, and maculopapular rash. One patient presented with diarrhea; no cases of colitis were reported. One patient discontinued treatment because of pyrexia and maculopapular rash; two patients died because of disease progression.

Conclusion

This study was terminated because factors contributing to safety concerns in phase III studies of idelalisib for hematological malignancies were not fully understood. In this small sample of patients with metastatic PDAC, exposure to idelalisib resulted in safety findings consistent with previous studies, with reduced diarrhea/colitis.

Discussion

Activation of PI3Kδ has been shown to be a key signal in immune suppression by increasing regulatory T cells and myeloid suppressor cells in cancer [1]. Targeting the PI3K pathway in PDAC may influence key components of the immunosuppressive tumor microenvironment [2]. Idelalisib, an oral potent inhibitor of PI3Kδ, was examined in individuals with metastatic PDAC in a phase Ib open‐label study (NCT02468557). Because of safety concerns observed in three phase III studies evaluating idelalisib as early‐line treatment for hematological malignancies (NCT01980888, NCT01732913, NCT01732926), the decision was made to terminate the phase Ib PDAC study. At termination, 12 patients were enrolled and received at least one dose of idelalisib in the single‐agent metastatic PDAC cohort (Table 1). With the exception of a reduced rate of diarrhea/colitis, observed treatment‐emergent adverse events were consistent with those reported in previous trials of idelalisib for hematological malignancies. Additional findings from this study are reported here.

Table 1.

Demographics and baseline characteristics

Demographics and baseline characteristics	Single‐agent idelalisib (n = 12), n (%)
Gender, female	6 (50.0)
Age, years
Mean (SD)	62 (10.7)
Median (range)	59 (40–77)
ECOG performance status
0	4 (33.3)
1	8 (66.7)
Time since diagnosis, mean (SD), years	1.4 (0.69)
Stage at diagnosis
I	0
II	5 (41.7)
III	1 (8.3)
IV	6 (50.0)
Stage at screening
I–III	0
IV	12 (100)
Time since completion of last regimen, months
Mean (SD)	1.1 (0.38)
Median (range)	1.0 (0.5–1.8)
Number of prior regimens
Mean (SD)	3 (1.1)
Median (range)	3 (1–5)
Best response to last regimen
PR	1 (8.3)
PD	4 (33.3)
Unable to evaluate	1 (8.3)
Unknown	6 (50.0)

Abbreviations: ECOG, Eastern Cooperative Oncology Group; PD, progressive disease; PR, partial response.

Trial Information

Disease	Pancreatic cancer
Stage of Disease/Treatment	Metastatic/advanced
Prior Therapy	No designated number of regimens
Type of Study	Phase I, adaptive design
Primary Endpoints	Safety, maximum tolerated dose
Secondary Endpoints	Pharmacokinetics, pharmacodynamics, efficacy
Additional Details of Endpoints or Study Design	This study was an adaptive dose‐escalating design with three planned treatment groups: single‐agent idelalisib, idelalisib combined with nab‐paclitaxel, and idelalisib combined with mFOLFOX6. Patients with relapsed‐refractory metastatic pancreatic ductal adenocarcinoma were to be enrolled to the single‐agent idelalisib and idelalisib + mFOLFOX6 arms. Patients with previously untreated metastatic pancreatic ductal adenocarcinoma were to be enrolled to the idelalisib + nab‐paclitaxel arm.
Investigator's Analysis	Because of early study termination, the prespecified efficacy analyses were not conducted.

Drug Information: Single‐Agent Idelalisib

Drug 1
Generic/Working Name	Idelalisib
Trade Name	Zydelig
Company Name	Gilead Sciences, Inc.
Drug Type	Small molecule
Drug Class	PI3 kinase
Dose	150 milligrams (mg) per flat dose
Route	Oral (p.o.)
Schedule of Administration	Twice daily (morning and evening). Each treatment cycle lasted 28 days.

Dose Escalation Table: Single‐Agent Idelalisib

Dose level	Dose of drug: idelalisib	Number enrolled	Number evaluable for toxicity
1	150 mg	16	12

Drug Information: Idelalisib + Nab‐Paclitaxel

Drug 1
Generic/Working Name	Idelalisib
Trade Name	Zydelig
Company Name	Gilead Sciences, Inc.
Drug Type	Small molecule
Drug Class	PI3 kinase
Dose	Milligrams (mg) per flat dose
Route	Oral (p.o.)
Schedule of Administration	Twice daily (morning and evening)
Drug 2
Generic/Working Name	Nab‐paclitaxel
Trade Name	Abraxane
Drug Type	Other
Drug Class	Microtubule‐targeting agent
Dose	125 milligrams (mg) per squared meter (m2)
Route	IV

Dose Escalation Table: Idelalisib + Nab‐Paclitaxel

Dose level	Dose of drug: idelalisib	Dose of drug: nab‐paclitaxel	Number enrolled	Number evaluable for toxicity
1	50 mg twice daily	125 mg/m2	0
2	100 mg twice daily	125 mg/m2	0
3	150 mg twice daily	125 mg/m2	0

Drug Information: Idelalisib + mFOLFOX6

Drug 1
Generic/Working Name	Idelalisib
Trade Name	Zydelig
Company Name	Gilead Sciences, Inc.
Drug Type	Small molecule
Drug Class	PI3 kinase
Dose	Milligrams (mg) per flat dose
Route	Oral (p.o.)
Schedule of Administration	Twice daily (morning and evening)
Drug 2
Generic/Working Name	5‐fluorouracil
Drug Type	Small molecule
Drug Class	Nucleobase analog
Dose	Milligrams (mg) per squared meter (m2)
Schedule of Administration	400 mg/m2 bolus, then 2,400 mg/m2 over 46 hours
Drug 3
Generic/Working Name	Leucovorin
Drug Type	Small molecule
Drug Class	Folinic acid
Dose	Milligrams (mg) per squared meter (m2)
Schedule of Administration	Levoleucovorin dose is 200 mg/m2. Racemic leucovorin dose is 400 mg/m2.
Drug 4
Generic/Working Name	Oxaliplatin
Drug Type	Small molecule
Drug Class	Platinum compound
Dose	85 milligrams (mg) per squared meter (m2)

Dose Escalation Table: Idelalisib + mFOLFOX6

Dose level	Dose of drug: idelalisib	Dose of drug: 5‐fluorouracil	Dose of drug: leucovorin	Dose of drug: oxaliplatin	Number enrolled	Number evaluable for toxicity
1	50 mg twice daily	400 mg/m2, then 2,400 mg/m2 over 46 hours	400 or 200 mg/m2	85 mg/m2	0
2	100 mg twice daily	400 mg/m2, then 2,400 mg/m2 over 46 hours	400 or 200 mg/m2	85 mg/m2	0
3	150 mg twice daily	400 mg/m2, then 2,400 mg/m2 over 46 hours	400 or 200 mg/m2	85 mg/m2	0

Patient Characteristics

Number of Patients, Male	6
Number of Patients, Female	6
Stage, n = 12	n (%)
Stage at diagnosis
I	0
II	5 (41.7)
III	1 (8.3)
IV	6 (50.0)
Stage at screening
I–III	0
IV	12 (100)
Age	Median (range): 59 (40–77)
Number of Prior Systemic Therapies	Median (range): 3 (1–5)
ECOG score
0	4 (33.3%)
1	8 (66.7%)
Other
Time since completion of last regimen, median (range), months	1.0 (0.5–1.8)
Best response to last regimen, n (%)
PR	1 (8.3)
PD	4 (33.3)
Unable to evaluate	1 (8.3)
Unknown	6 (50.0)

Abbreviations: PD, progressive disease; PR, partial response.

Cancer Types or Histologic Subtypes

Pancreatic ductal adenocarcinoma, 12

Primary Assessment Method

Title	Tumor biopsy and computed tomography/magnetic resonance imaging
Number of Patients Screened	35
Number of Patients Enrolled	16
Number of Patients Evaluable for Toxicity	12
Number of Patients Evaluated for Efficacy	0
Evaluation Method	RECIST 1.1

Adverse Events

All Cycles
Name	NC/NA, %	Grade 1, %	Grade 2, %	Grade 3, %	Grade 4, %	Grade 5, %	All grades, %
Epistaxis	92	8	0	0	0	0	8
Abdominal pain	83	17	0	0	0	0	17
Aspartate aminotransferase increased	58	0	0	42	0	0	42
Insomnia	83	17	0	0	0	0	17
Acute kidney injury	92	0	0	8	0	0	8
Ascites	92	8	0	0	0	0	8
Arthralgia	92	8	0	0	0	0	8
Alkaline phosphatase increased	92	8	0	0	0	0	8
Blood bilirubin increased	92	8	0	0	0	0	8
Dehydration	92	0	0	8	0	0	8
Chills	84	8	8	0	0	0	16
Diarrhea	92	8	0	0	0	0	8
Fatigue	92	8	0	0	0	0	8
Constipation	83	17	0	0	0	0	17
Hyponatremia	92	0	0	8	0	0	8
Hypertension	92	8	0	0	0	0	8
Nausea	92	0	8	0	0	0	8
Pruritus	92	8	0	0	0	0	8
Small intestinal obstruction	92	0	0	8	0	0	8
Upper gastrointestinal hemorrhage	92	0	0	8	0	0	8
Urinary tract obstruction	92	8	0	0	0	0	8
Weight loss	92	8	0	0	0	0	8
Rash maculopapular	75	0	0	25	0	0	25
Dizziness	92	8	0	0	0	0	8
Generalized muscle weakness	92	0	8	0	0	0	8
Hematuria	83	17	0	0	0	0	17
Vomiting	83	17	0	0	0	0	17
Alanine aminotransferase increased	67	0	8	25	0	0	33

Abbreviation: NC/NA, no change from baseline/no adverse event.

Adverse Events Legend

n = 12. Treatment‐emergent adverse events were classified by preferred term (PT) using MedDRA version 19.0. Subjects who experienced multiple events within the same PT are counted once per PT.

Pharmacokinetics/Pharmacodynamics

Cycle, day, sampling time, h	n	Mean (SD), ng/mL	% CV
Cycle 1, day 1
Predose	7	Below the limit of quantitation
0.5	3	1,448.0 (1,629.6)	112.5
1.0	3	1,993.0 (2,012.8)	101.0
1.5	11	1,758.8 (1,712.6)	97.4
2.0	3	1,974.3 (2,223.9)	112.6
3.0	3	1,432.0 (1,248.0)	87.2
4.0	3	1,349.7 (753.7)	55.9
8.0	3	379.3 (328.9)	86.7
Cycle 1, day 8
Predose	8	350.8 (199.4)	56.8
1.5	8	2,209.9 (1,190.3)	53.9
Cycle 1, day 15
Predose	3	545.3 (498.0)	91.3
1.5	4	1,650.0 (560.3)	34.0
Cycle 2, day 1
Predose	4	160.0 (143.3)	89.6
1.5	4	2,460.0 (971.1)	39.5

Abbreviation: CV, coefficient of variation.

Assessment, Analysis, and Discussion

Completion	Study terminated before completion
Terminated Reason	Company stopped development
Investigator's Assessment	Because of early study termination, the prespecified efficacy analyses were not conducted.

Pancreatic ductal adenocarcinoma (PDAC) is the seventh leading cause of cancer mortality worldwide with almost as many annual deaths (n = 432,000) as cases (n = 459,000) [3]. Early stage pancreatic cancer is often clinically silent, resulting in diagnoses at an advanced stage with 80%–90% of patients presenting with unresectable tumors [4, 5]. The current recommended treatment protocols for patients with metastatic pancreatic cancer include regimens of FOLFIRINOX (folinic acid, 5‐fluorouracil, irinotecan, and oxaliplatin), modified FOLFIRINOX, or gemcitabine plus nanoparticle albumin‐bound (nab)‐paclitaxel as first‐line therapeutic options [6]. Median overall survival (OS) of FOLFIRINOX in metastatic PDAC is 11.1 months with an objective response rate (ORR) of 31.6% [7]. Median OS for gemcitabine plus nab‐paclitaxel is 8.5 months with an ORR of 23% [8]. Therefore, a critical need for development of effective treatment remains [9].

Based on phase II and III studies, idelalisib—a potent, selective, small molecule inhibitor of phosphatidylinositol‐3 kinase (PI3K) δ—was approved for the treatment of relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, and for patients with relapsed follicular lymphoma or relapsed small lymphocytic lymphoma who have received at least two prior systemic therapies [10, 11, 12].

Recent studies of PI3K inhibition in patients with solid tumors, such as breast cancer, are equally encouraging [13, 14, 15]. The PI3Kα inhibitor, alpelisib, combined with fulvestrant significantly reduced the risk of tumor progression or death by 35% compared with placebo plus fulvestrant in patients with progressed hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative, PIK3CA‐mutated breast cancer [14]. Similarly, significant improvement of progression‐free survival, ORR, and clinical benefit were observed in treatment of HR‐positive, HER2‐negative inoperable locally advanced or metastatic breast cancer treated with the pan‐PI3K inhibitor, buparlisib, used in combination with fulvestrant, when compared with fulvestrant alone [15].

In preclinical studies, regulatory T (Treg) cells, CD4⁺ T cells, and CD8⁺ T cells are increased in malignant PDAC tissue compared with healthy tissue. Treg cells may stimulate PDAC progression by inhibiting the cytotoxic effects of CD8⁺ T cells [9]. As a result, increased numbers of Treg cells in tumor tissue may indicate suppressed antitumor immunity and a poor prognosis [15]. PI3Kδ inhibition disrupts the function of both Treg cells and myeloid‐derived suppressor cells (MDSCs) to promote antitumor immunity in preclinical tumor models, lending support to the use of PI3Kδ inhibitors in patients with PDAC [2]. Fibroblast expression of PIK3Cδ, a subunit of PI3K, was identified as a key regulator of tumor progression in preclinical models of triple negative breast cancer [16]. PI3K is also an upstream activator of the serine/threonine kinase AKT, which is increased in ~59% of pancreatic tumors [17]. Moreover, there is a significant correlation between increased activation of AKT and a high histologic tumor grade, suggesting that AKT may be a marker of aggressive tumor behavior [17].

Study GS‐US‐385‐1577 was a phase Ib, open‐label clinical study of idelalisib for metastatic PDAC (mPDAC) conducted in the U.S. (NCT02468557). There were three treatment groups: single‐agent idelalisib for refractory mPDAC, combination of idelalisib with nab‐paclitaxel for untreated mPDAC, and combination of idelalisib with modified (m)FOLFOX6 for refractory mPDAC. Primary objectives were to define the maximum tolerated dose of idelalisib when used in combination with chemotherapy and to evaluate the safety of single‐agent idelalisib. Secondary objectives included the pharmacokinetics, pharmacodynamics, and efficacy of idelalisib alone or in combination with chemotherapy. The study was terminated early because of an increased rate of deaths and serious adverse events (AEs) identified in phase III placebo‐controlled studies of idelalisib as first‐line treatment for CLL (NCT01980888) and early‐line treatment for indolent non‐Hodgkin's lymphoma (NCT01732913, NCT01732926). The sponsor ended this study and other ongoing studies of idelalisib in agreement with the independent data monitoring committee's recommendation and in consultation with the U.S. Food and Drug Administration.

At termination, 16 patients were enrolled in the idelalisib monotherapy group; of these, 12 patients received at least one dose of idelalisib 150 mg twice daily. No patients were enrolled in the idelalisib plus nab‐paclitaxel or idelalisib plus mFOLFOX6 groups. At baseline, patients had a median of three prior treatments (Table 1). Of the 12 patients dosed, 5 (41.7%) discontinued idelalisib because of disease progression, 1 (8.3%) discontinued because of AEs of pyrexia and maculopapular rash, and the remaining 6 patients (50%) discontinued because of study termination. The median duration of idelalisib exposure was 3.1 (range 0.4–8.0) weeks.

Frequent (≥25%) treatment‐emergent AEs (TEAEs) included pyrexia (50%), increased aspartate aminotransferase (AST; 41.7%), increased alanine aminotransferase (ALT; 33.3%), and maculopapular rash (25%). Common (≥25%) grade ≥ 3 TEAEs were increased AST (41.7%), increased ALT (25%), and maculopapular rash (25%) (Table 2). Treatment‐emergent serious AEs related to idelalisib were reported in two patients and included pyrexia (n = 1), increased ALT (n = 1) or AST (n = 1), and maculopapular rash (n = 1) (Table 3 and 4). Two patient deaths occurred during the study period because of disease progression. Adverse events of interest associated with idelalisib treatment include diarrhea and colitis. Diarrhea occurred in 1 of 12 patients (8.3%), and no cases of colitis were reported.

Table 2.

Summary of all treatment‐emergent adverse events separated by grade

Preferred term	Single‐agent idelalisib (n = 12), n (%)
	Grade 1	Grade 2	Grade 3	Total
Pyrexia	4 (33.3)	2 (16.7)	0	6 (50.0)
AST increased	0	0	5 (41.7)	5 (41.7)
ALT increased	0	1 (8.3)	3 (25.0)	4 (33.3)
Rash maculopapular	0	0	3 (25.0)	3 (25.0)
Abdominal pain	2 (16.7)	0	0	2 (16.7)
Chills	1 (8.3)	1 (8.3)	0	2 (16.7)
Constipation	2 (16.7)	0	0	2 (16.7)
Hematuria	2 (16.7)	0	0	2 (16.7)
Insomnia	2 (16.7)	0	0	2 (16.7)
Rash	2 (16.7)	0	0	2 (16.7)
Vomiting	2 (16.7)	0	0	2 (16.7)
Abdominal discomfort	0	1 (8.3)	0	1 (8.3)
Abdominal pain upper	0	1 (8.3)	0	1 (8.3)
Acute kidney injury	0	0	1 (8.3)	1 (8.3)
Ascites	1 (8.3)	0	0	1 (8.3)
Aphasia	0	1 (8.3)	0	1 (8.3)
Arthralgia	1 (8.3)	0	0	1 (8.3)
Bacteremia	0	1 (8.3)	0	1 (8.3)
Blood alkaline phosphatase increase	1 (8.3)	0	0	1 (8.3)
Blood bilirubin increase	1 (8.3)	0	0	1 (8.3)
Chromaturia	1 (8.3)	0	0	1 (8.3)
Coagulopathy	0	0	1 (8.3)	1 (8.3)
Decreased appetite	1 (8.3)	0	0	1 (8.3)
Dehydration	0	0	1 (8.3)	1 (8.3)
Diabetes mellitus inadequate control	0	0	1 (8.3)	1 (8.3)
Diarrhea	1 (8.3)	0	0	1 (8.3)
Dizziness	1 (8.3)	0	0	1 (8.3)
Epistaxis	1 (8.3)	0	0	1 (8.3)
Fatigue	1 (8.3)	0	0	1 (8.3)
Hemoptysis	1 (8.3)	0	0	1 (8.3)
Hypertension	1 (8.3)	0	0	1 (8.3)
Hypoesthesia	0	1 (8.3)	0	1 (8.3)
Hyponatremia	0	0	1 (8.3)	1 (8.3)
Muscular weakness	0	1 (8.3)	0	1 (8.3)
Nausea	0	1 (8.3)	0	1 (8.3)
Onycholysis	1 (8.3)	0	0	1 (8.3)
Paresthesia	1 (8.3)	0	0	1 (8.3)
Pruritis	1 (8.3)	0	0	1 (8.3)
Rash macular	1 (8.3)	0	0	1 (8.3)
Rectal spasm	1 (8.3)	0	0	1 (8.3)
Small intestinal obstruction	0	0	1 (8.3)	1 (8.3)
Upper gastrointestinal hemorrhage	0	0	1 (8.3)	1 (8.3)
Urinary tract obstruction	1 (8.3)	0	0	1 (8.3)
Weight decrease	1 (8.3)	0	0	1 (8.3)
Xerosis	1 (8.3)	0	0	1 (8.3)

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Table 3.

SAEs by preferred term

Preferred term	Single‐agent idelalisib (n = 12), n (%)
Patients with any treatment‐emergent SAE	3 (25.0)
SAE by preferred term
Acute kidney injury	1 (8.3)
ALT increased	1 (8.3)
AST increased	1 (8.3)
Coagulopathy	1 (8.3)
Dehydration	1 (8.3)
Diabetes mellitus inadequate control	1 (8.3)
Pyrexia	1 (8.3)
Rash maculopapular	1 (8.3)
Small intestinal obstruction	1 (8.3)
Upper gastrointestinal hemorrhage	1 (8.3)

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; SAE, serious adverse event.

Table 4.

Overall summary of TEAEs

Safety parameter	Single‐agent idelalisib (n = 12), n (%)
Any TEAE	12 (100.0)
Grade ≥ 3	7 (58.3)
Related to IDL	8 (66.7)
Related to IDL and grade ≥ 3	5 (41.7)
Serious TEAE	3 (25.0)
Related to IDL	2 (16.7)
TEAE leading to dose reduction	0
TEAE leading to IDL interruption	4 (33.3)
TEAE leading to IDL discontinuation	1 (8.3)
TEAE leading to death	0
Deaths up to 30 days after end of study	2 (16.7)

Abbreviations: IDL, idelalisib; TEAE, treatment‐emergent adverse event.

Although the investigation of idelalisib in patients with PDAC was dissolved early, evaluating the efficacy of PI3K inhibitors as a therapeutic option is warranted. Further studies evaluating the effects of PI3K inhibition in PDAC should include the utilization of on‐treatment paired biopsies to determine the effects of PI3K inhibition in relation to Treg cell and MDSC populations. Peripheral blood assays may be used as a corollary to tissue analyses in examining the effect of PI3K inhibition [18]. In comparison with previous studies, AST and ALT values were elevated, whereas diarrhea and colitis were lower or not observed [11, 12, 19]. The observed AST and ALT elevations may be due to the nature of mPDAC itself, as most individuals have liver metastasis [20]; however, the small sample size may also have inflated the rate of these TEAEs. Although limited, this study suggests that idelalisib may produce a different safety profile in patients with mPDAC as compared with previous studies of patients with hematologic malignancies.

Disclosures

Erkut Borazanci: Imaging Endpoints (C/A), Ipsen (H), Bristol‐Myers Squibb, Daiichi Sankyo, Eli Lilly, Idera, Merck, Minneamrita, Pharmacyclics LLC (an AbbVie Company), Pfizer, Samumed (RF); Michael J. Pishvaian: Merck, AstraZeneca, Perthera, Sirtex, Foundation Medicine, Halozyme (C/A), ARMO BioSciences (Inst), Bavarian Nordic, Bayer (Inst), AstraZeneca, Bristol‐Myers Squibb (Inst), Calithera Biosciences (Inst), Celgene (Inst), Celldex (Inst), Curegenix (Inst), FibroGen (Inst), Genentech (Inst), Gilead Sciences (Inst), GlaxoSmithKline (Inst), Halozyme (Inst), Karyopharm Therapeutics (Inst), MedImmune (Inst), Merck (Inst), Novartis (Inst), Pfizer (Inst), Pharmacyclics (Inst), Regeneron (Inst), Tesaro (Inst) (RF), AstraZeneca/MedImmune, Caris Life Sciences, Perthera, Celgene, Merrimack, Sirtex Medical (H, Other: travel expenses), Perthera, Inc. (OI, IP); John Nemunaitis: Gradalis (E, OI, IP), Amgen, AstraZeneca (C/A, H, SAB); Amgen, AstraZeneca, Baxalta, Takeda (Other: travel); Colin Weekes: Celgene, Merrimack (C/A), Bayer, Celgene, Lilly, Merrimack (H), Abbvie, AstraZeneca, Bayer, Celgene, Genentech/Roche, Gilead Sciences, Halozyme, Ipsen, Lilly, Millennium (RF), Bayer, Celgene, Lilly (Other: travel); Julie Huang: Gilead Sciences (E, OI); Nishanthan Rajakumaraswamy: Gilead Sciences (E, OI).

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board