A Phase II Study of Duvelisib Plus Docetaxel in PD-1 Inhibitor Experienced Patients With Incurable Head and Neck Squamous Cell Carcinoma
Phase: PHASE2
Conditions: Squamous Cell Carcinoma of the Head and Neck (SCCHN), Recurrent Squamous Cell Carcinoma of the Head and Neck, Metastatic Head and Neck Cancer, Advanced Head and Neck Cancer, Advanced Head and Neck Squamous Cell Carcinoma
Sponsor: Glenn J. Hanna

 
 
 
 
 
 
 
 
 
Title: A phase II study of duvelisib plus docetaxel in PD-1 inhibitor experienced 
patients with incurable head and neck squamous cell carcinoma 
NCT Number: NCT05057247 
IRB Approval Date: 11/29/2021 

NCI Protocol #: Not applicable 
DF/HCC Protocol #: 21-393 
TITLE: A phase II study of duvelisib plus docetaxel in PD-1 inhibitor experienced patients 
with incurable head and neck squamous cell carcinoma 
 
Coordinating Center: 
Dana-Farber Cancer Institute, 
450 Brookline Avenue, Boston, MA 02215 
 
Sponsor-Investigator (PI): 
Glenn J. Hanna, M.D. 
Dana-Farber Cancer Institute 
glenn_hanna@dfci.harvard.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Agents: Duvelisib (VS-0145; Copiktra); Docetaxel, Taxotere or Docefrez 
IND Holder: Glenn J. Hanna, M.D. 
IND Number: 156639 
Protocol Type / Version # / Version Date: November 17, 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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SCHEMA 

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TABLE OF CONTENTS 
SCHEMA ................................................................................................................................................................................ 1 
1. 
OBJECTIVES .............................................................................................................................................................. 5 
1.1 
STUDY DESIGN ............................................................................................................................... 5 
1.2 
PRIMARY OBJECTIVES ................................................................................................................... 5 
1.3 
SECONDARY OBJECTIVES .............................................................................................................. 5 
2. 
BACKGROUND .......................................................................................................................................................... 5 
2.1 
STUDY DISEASE(S) ......................................................................................................................... 5 
2.2 
IND AGENT: DUVELISIB ................................................................................................................ 6 
2.3 
OTHER AGENT: DOCETAXEL ......................................................................................................... 8 
2.4 
RATIONALE..................................................................................................................................... 9 
2.5 
CORRELATIVE STUDIES BACKGROUND ...................................................................................... 10 
3. 
PARTICIPANT SELECTION ................................................................................................................................. 12 
3.1 
ELIGIBILITY CRITERIA ................................................................................................................. 12 
3.2 
EXCLUSION CRITERIA .................................................................................................................. 13 
3.3 
INCLUSION OF WOMEN AND MINORITIES ................................................................................... 14 
4. 
REGISTRATION PROCEDURES .......................................................................................................................... 14 
4.1 
GENERAL GUIDELINES FOR DF/HCC INSTITUTIONS ................................................................. 14 
4.2 
REGISTRATION PROCESS FOR DF/HCC INSTITUTIONS .............................................................. 14 
4.3 
GENERAL GUIDELINES FOR OTHER INVESTIGATIVE SITES ....................................................... 15 
4.4 
REGISTRATION PROCESS FOR OTHER INVESTIGATIVE SITES..................................................... 15 
5. 
TREATMENT PLAN ................................................................................................................................................ 15 
5.1 
TREATMENT REGIMEN ................................................................................................................. 15 
5.2 
PRE-TREATMENT CRITERIA ........................................................................................................ 16 
5.3 
CHEMOTHERAPY AND TARGETED THERAPY ADMINISTRATION ................................................ 19 
5.4 
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ....................... 19 
5.5 
CRITERIA FOR TAKING A PARTICIPANT OFF PROTOCOL THERAPY ........................................... 21 
5.6 
DURATION OF FOLLOW-UP ......................................................................................................... 22 
5.7 
CRITERIA FOR TAKING A PARTICIPANT OFF STUDY .................................................................. 22 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...................................................................................................... 22 
6.1 
DUVELISIB .................................................................................................................................... 23 
6.2 
DOCETAXEL.................................................................................................................................. 25 
6.3 
RECOMMENDED DOSE MODIFICATIONS FOR THE MANAGEMENT OF OVERLAPPING 
TOXICITIES FOR DUVELISIB IN COMBINATION WITH DOCETAXEL ......................................................... 26 
6.4 
UNACCEPTABLE TOXICITY .......................................................................................................... 26 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS................................................................ 27 
7.1 
EXPECTED TOXICITIES ................................................................................................................. 27 
7.2 
ADVERSE EVENT CHARACTERISTICS .......................................................................................... 27 
7.3 
ADVERSE EVENT REPORTING...................................................................................................... 28 
7.4 
DF/HCC ADVERSE EVENT REPORTING GUIDELINES ................................................................ 29 

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7.5 
REPORTING TO THE FOOD AND DRUG ADMINISTRATION (FDA) .............................................. 30 
7.6 
REPORTING TO HOSPITAL RISK MANAGEMENT ......................................................................... 30 
7.7 
REPORTING TO THE SECURA BIO................................................................................................. 30 
7.8 
ROUTINE ADVERSE EVENT REPORTING ..................................................................................... 30 
8. 
PHARMACEUTICAL INFORMATION................................................................................................................ 30 
8.1 
STUDY AGENT: DUVELISIB .......................................................................................................... 30 
8.2 
DOCETAXEL.................................................................................................................................. 31 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ............................................................................ 32 
10. 
STUDY CALENDAR ................................................................................................................................................ 33 
11. 
MEASUREMENT OF EFFECT .............................................................................................................................. 35 
11.1 
ANTITUMOR EFFECT – SOLID TUMORS ....................................................................................... 35 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ............................................................................... 40 
12.1 
DATA REPORTING ........................................................................................................................ 40 
12.2 
DATA SAFETY MONITORING ....................................................................................................... 41 
12.3 
MULTI-CENTER GUIDELINES ...................................................................................................... 41 
13. 
STATISTICAL CONSIDERATIONS ..................................................................................................................... 41 
13.1 
STUDY DESIGN/ENDPOINTS ......................................................................................................... 41 
13.2 
SAMPLE SIZE AND ACCRUAL RATE ............................................................................................ 42 
13.3 
STRATIFICATION FACTORS .......................................................................................................... 42 
13.4 
INTERIM MONITORING PLAN ....................................................................................................... 42 
13.5 
ANALYSIS OF PRIMARY ENDPOINT ............................................................................................. 42 
13.6 
ANALYSIS OF SECONDARY ENDPOINTS ...................................................................................... 42 
14. 
PUBLICATION PLAN.............................................................................................................................................. 43 
15. 
REFERENCES ........................................................................................................................................................... 43 
16. 
APPENDIX A PERFORMANCE STATUS CRITERIA....................................................................................... 45 
19. 
APPENDIX B MULTICENTER PROTOCOL GUIDELINES............................................................................ 53 

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1. OBJECTIVES 
 
1.1 
Study Design 
 
This multicenter, phase II open-label, single-arm trial will enroll patients with recurrent or metastatic 
(R/M), incurable squamous cell carcinoma of the head and neck (SCCHN) who have failed or 
discontinued PD-1 blockade in the first-line (1L) advanced disease setting, regardless of human 
papillomavirus (HPV) and smoking status, or PI3K pathway alteration status. Participants with or 
without a prior response to immune checkpoint blockade are permitted, to include individuals with 
both inherent and acquired immune resistance. Prior taxane (paclitaxel only) exposure as part of 1L 
chemoimmunotherapy is permitted, but not required. Patients will receive duvelisib 25 mg by mouth 
twice daily continuously (days 1-21 of a 21-day cycle) with a 7-day lead-in planned prior to the start 
of taxane therapy. Docetaxel at 75 mg/m2 IV will be delivered on day 1 of each 21-day cycle. 
Treatment will continue for 24-months or until unacceptable toxicity, progression, or death. 
 
1.2 
Primary Objectives 
 
To evaluate the anti-tumor activity of duvelisib plus docetaxel chemotherapy by evaluating the best 
overall response rate using RECIST v1.1 in participants with R/M SCCHN who have received prior 
(chemo)immunotherapy. 
 
1.3 
Secondary Objectives 
 
• To estimate progression-free survival (PFS) and overall survival (OS) 
• To estimate duration of therapeutic response 
• To evaluate safety and tolerability of the combination 
• To characterize patient-reported outcome (PRO) qualify of life metrics 
• To correlate tumor genomic/molecular and immunologic phenotype (TP53, PI3K pathway 
alteration status; PD-L1 score) with response 
2. BACKGROUND 
 
2.1 
Study Disease(s) 
 
Squamous cell carcinoma of the head and neck (SCCHN) represents over 90% of all head and neck 
malignancies. Although the majority of patients present with locoregionally advanced disease, the 
clinical course is characterized by a high rate of recurrence approaching 50%, as well as the 
development of distal metastases [1-3]. The median survival in most series ranges from 6 to 15 
months depending on patient-related and disease-related factors. Immune checkpoint inhibitors 
targeting PD-1 have redefined the treatment of advanced or recurrent or metastatic (R/M), incurable 
SCCHN [4-7] where outcomes are generally poor. However, objective response rates remain around 
30-40% even in the first-line (1L) advanced disease setting with chemotherapy (carboplatin plus 5- 
fluorouracil, PF) combined with PD-1 blockade (pembrolizumab) [7]. Pembrolizumab (PD-1 
inhibitor) is also approved as a single agent for 1L treatment of patients with metastatic or with 
unresectable, recurrent SCCHN whose tumors overexpress the tumor immune marker PD-L1 

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(combined positive score [CPS] ≥1) and was approved in combination with PF for all patients. In 
subjects with CPS ≥1, overall survival (OS) was significantly longer with pembrolizumab 
monotherapy vs. standard of care PF-cetuximab therapy (12.3 vs. 10.3 months, HR 0.78, p=0.01) in 
the recent landmark KEYNOTE-048 study. Objective response rate and median duration of response 
(DOR) were 19% and 20.9 months in the pembrolizumab monotherapy group vs. 35% and 4.5 
months in the standard chemotherapy group, respectively. In addition, both pembrolizumab and 
nivolumab are approved in the platinum-refractory setting for advanced SCCHN [8, 9]. 
 
Since 1L (chemo)immunotherapy was approved in 2019 for SCCHN, available second-line (2L) 
treatment options consist of pre-immunotherapy era cytotoxic agents and epidermal growth factor 
receptor (EGFR) antibody therapy with limited response rates (frequently <15%) and unfavorable 
toxicity profiles as summarized in Table 1 below. 
 
Table 1. Efficacy and survival data with the use of systemic therapy after platinum-based chemotherapy in advanced, 
recurrent SCCHN 
Trial 
Agent(s) 
Line of 
Therapy 
N 
ORR 
PFS 
OS 
Grade 3-4+ 
toxicity 
Specenier P, 
et al. 2011 
Weekly 
docetaxel 
2L+ 
30 
6.7% 
(2/30) 
7.4 weeks 
17.9 weeks 
no grade 4 
Catimel G, 
et al. 1994 
Gemcitabine 
1-2L+ 
61 
13% (7/61) 
-- 
-- 
< 10% 
Vermorken 
JB, et al. 
2007 
Cetuximab 
2L+ 
103 
13% 
-- 
178 days 
dermatitis 
Machiels JP, 
et al. 2015 
Afatinib 
Methotrexate 
2L+ 
322 
161 
10% 
6% 
2.6 months 
1.7 months 
6.8 months 
6 months 
rash, 
diarrhea 
Stewart JS, 
et al. 2009 
Gefitinib 
Methotrexate 
1L+ 
167 
161 
2.7-7.6% 
3.9% 
-- 
5.6-6 
months 
6.7 months 
rash, 
diarrhea 
ORR = overall response rate, PFS = progression-free survival, OS = overall survival 
 
2.2 
IND Agent: Duvelisib 
 
2.2.1 
Duvelisib 
 
2.2.1.1 
Mechanism of action 
 
Duvelisib (VS-0145) is a synthetic, orally-active, small molecule dual inhibitor of phosphoinositide 
3-kinase (PI3K)-δ and PI3K-γ isoforms that reduces the cancer-promoting effects of both isoforms 
through effects on the tumor microenvironment (TME) and has an established clinical safety and 
efficacy profile in patients with hematologic malignancies. Duvelisib is approved for the treatment 
of adult patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small 
lymphocytic lymphoma (SLL) after at least two prior systemic therapies and was granted accelerated 
approval in adult patients with follicular lymphoma (FL) after at least two prior systemic therapies 
[10]. Duvelisib is being developed by Secura Bio, Inc. (Secura Bio). 
 
While the tumor-suppressing effect of duvelisib in hematologic malignancies is well established [11, 
12], a direct effect of duvelisib and PI3K signaling on tumor cell proliferation and survival has not 
been well characterized in solid tumors. However, because of the significant presence of immune 

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cells in the TME, a cell-based target for duvelisib is thought to be the immunomodulating TME 
consisting of T cell, B cell, and myeloid lineage cells, in particular. 
 
2.2.1.2 
Clinical pharmacology and safety 
 
A phase I trial of duvelisib in preclinical models and patients with T-cell lymphoma (TCL) was 
conducted among 35 patients along with in vitro and in vivo models with a primary endpoint of 
overall response rate [14]. The most frequent reported observed grade 3-4 adverse events were 
transaminase increases (40% alanine aminotransferase, 17% aspartate aminotransferase), 
maculopapular rash (17%), and neutropenia (17%). 
In a large, randomized (1:1), multicenter, open-label trial (NCT02004522; DUO trial) comparing 
duvelisib to ofatumumab in 319 patients with relapsed or refractory CLL, duvelisib was dosed 25 mg 
orally twice daily [15]. The prescribing information contains boxed warnings for fatal and/or serious 
infections in the hematologic malignancy population, diarrhea or colitis, cutaneous reactions, and 
pneumonitis; and warnings for neutropenia and hepatotoxicity. Of a total of 442 patients with 
hematologic malignancies treated with duvelisib at the approved dose, 65% had serious adverse 
reactions, with the most frequent being infection, diarrhea or colitis, and pneumonia. The most 
common adverse reactions (incidence ≥20%) were diarrhea or colitis, neutropenia, rash, fatigue, 
pyrexia, cough, nausea, upper respiratory infection, pneumonia, musculoskeletal pain, and anemia. 
Adverse reactions resulted in permanent discontinuation of duvelisib in 35% of patients. Dose 
reduction occurred in 24% of those receiving duvelisib. 
To assess possible direct effects of duvelisib on solid tumor cells, the growth inhibitory activity of 
duvelisib has been evaluated across 7 melanoma and 3 SCCHN cell lines expressing high levels of 
PI3K-δ and/or PI3K-γ [16]. Cell viability was measured after 72-hour treatment with duvelisib 
(0.5nM-10μM) and reported as growth inhibition (GI) at 1μM. Duvelisib showed strong anti- 
proliferative activity (50-100% GI) in 3 out of 7 melanoma cell lines and 1 out of 3 SCCHN cell 
lines, and moderate activity (15-50% GI) in 3 melanoma cell lines and an additional SCCHN cell 
line. Duvelisib inhibited PI3K pathway activity, as measured by p-AKT and c-myc, in all the cell 
lines in which strong anti-proliferative activity was observed. Taken together, these findings indicate 
that in addition to the established effects of duvelisib on malignant B cells and non-malignant 
immune cells of the TME, duvelisib can also directly inhibit signaling and proliferation of solid 
tumor cells expressing PI3K-δ and/or PI3K-γ, providing further rationale for clinical investigation of 
duvelisib for the treatment of solid tumors. 
2.2.1.3 
Clinical efficacy 
 
The CLL indication is based on the randomized, multicenter, open-label DUO trial, which compared 
duvelisib with ofatumumab (Arzerra) in patients with relapsed or refractory CLL (NCT02004522) 
[13]. The trial randomized patients (1:1) to receive either duvelisib at 25 mg orally twice daily (the 
recommended dose) or ofatumumab. Among 196 patients receiving at least 2 prior therapies, the 
estimated median progression-free survival (PFS) as assessed by an independent review committee 
was 16.4 months with duvelisib and 9.1 months with ofatumumab. The overall response rate per 
independent review committee was 78% and 39% for the duvelisib and ofatumumab arms, 
respectively. 

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In the DYNAMO trial, 129 patients with any refractory, indolent non-Hodgkin lymphoma (NHL) 
(FL, CLL, or marginal zone B-cell lymphoma) were treated with duvelisib 25 mg orally twice daily 
in 28-day cycles showing an ORR of 47.3% with a median DOR of 10 months; and the median PFS 
was 9.5 months [17]. 
 
The follicular lymphoma (FL) indication is based on the single-arm multicenter DYNAMO + R trial 
of duvelisib, which enrolled 83 patients with FL whose disease was refractory to rituximab (Rituxan) 
and either chemotherapy or radioimmunotherapy (NCT02204982) [18]. The overall response rate, 
determined by an independent review committee, was 42%, with 41% of patients experiencing 
partial responses. Of the 35 responding patients, 15 (43%) maintained responses for at least 6 
months, and 6 (17%) maintained responses for at least 12 months. 
 
Beyond hematologic malignancies, the anti-tumor activity of duvelisib is now being assessed in solid 
tumors. 
 
2.3 
Other Agent: Docetaxel 
 
2.3.1 
Docetaxel 
 
2.3.1.1 
Mechanism of action 
 
Docetaxel promotes the assembly of microtubules from tubulin dimers, and inhibits the 
depolymerization of tubulin which stabilizes microtubules in the cell. This results in inhibition of 
DNA, RNA, and protein synthesis. Most activity occurs during the M phase of the cell cycle. 
 
2.3.1.2 
Clinical pharmacology and safety 
 
Docetaxel (Taxotere®) was first approved for use by the US Food and Drug Administration in 1996 
for locally advanced or metastatic breast cancer after failure of prior chemotherapy, with a dose of 
60 to 100 mg/m2 administered intravenously over 1 hour every 3 weeks. Thereafter, additional 
indications were approved at a dose of 75 mg/m2 [19]. In a phase I trial, the PK of docetaxel was 
linear, determined by 23 patients receiving 20–115 mg/m2. At high doses of docetaxel (85–115 
mg/m2), a three-compartment model was found to provide a better fit than a two-compartment model 
with a terminal half-life of 13.5 ± 7.5 h (mean ± SD), a plasma clearance of 21.1 ± 5.3 L/h/m2 and a 
distribution volume of 72 ± 40 L/m [20]. Docetaxel exposure as measured by the area under the 
plasma concentration time curve (AUC) was the only significant predictor of severe toxicity during 
the first course of chemotherapy. It was also reported that docetaxel PK were similar for weekly and 
3-weekly regimens [21]. Short-lasting neutropenia is the dose-limiting toxicity. Other common but 
non-dose-limiting toxicities are mucositis, alopecia, fatigue, sensory peripheral neuropathy, fluid 
retention, rash, and acute hypersensitivity reactions. Studies have confirmed that dexamethasone as 
prophylaxis against hypersensitivity reactions and fluid retention is both warranted and effective 
with docetaxel use. 
2.3.1.3 
Clinical efficacy 
 
Several groups first reported on the activity of docetaxel as a single agent in SCCHN in the late 
1990s. Two published trials, conducted by the Dana-Farber Cancer Institute in Boston and the early 

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trials of the European Organization for Research and Treatment of Cancer (EORTC), treated a total 
of 75 patients with docetaxel monotherapy at 100 mg/m2 every 21 days [22, 23]. Patients enrolled on 
these trials were of good performance status and had not been previously treated with palliative 
chemotherapy, although approximately one third of the patients had previously received induction 
chemotherapy. Of 68 assessable patients, six (9%) achieved a complete response and 21 (31%) a 
partial response. 
 
After cetuximab with platinum-based 5-fluorouracil (5-FU) containing chemotherapy was 
established as the former 1L standard combination (EXTREME regimen) for R/M SCCHN [24] 
prior to the era of immunotherapy, the taxane docetaxel was later exchanged for 5-FU in the TPEx 
regimen [25] and among 539 patients randomized 1:1 showed comparable OS between groups 
(HR=0.87, p=0.15) with 2-year OS rates that were similar (28.6 vs. 21% favoring the docetaxel- 
containing combination) with overall less toxicity. A number of other docetaxel-platinum core 
combination regimens have shown encouraging activity in advanced SCCHN [26] (Table 2). 
 
Table 2. Efficacy and survival data with the use of docetaxel-containing chemotherapy regimens in advanced, recurrent 
SCCHN 
Trial 
Agent(s) 
N 
ORR 
2-year OS 
Median OS 
Gedlicka, 
et al. 2002 
D (75 mg/m2) + C (75 mg/m2) q21d 
38 
52.5% 
9% 
11.0 (1-30) 
Yabuuchi, 
et al. 2003 
D (60 mg/m2) + C (70 mg/m2) 
17 
71% 
-- 
-- 
Hehr, et 
al. 2005 
D (50 mg/m2) + C (15 mg/m2 days 2-5) 
q21d + 2Gy RT daily 
39 
80% 
20% 
10.0 
Baghi, et 
al. 2006 
D (75 mg/m2) + C (100 mg/m2) + 5- 
fluorourail (1 g/m2 d1-4) q21d 
24 
42% 
-- 
13.0 
Peyrade, 
et al. 2006 
D (75 mg/m2) + C (75 mg/m2) + 5- 
fluorourail (750 mg/m2 d2-5) q21d 
40 
63% 
-- 
13.0 
ORR = overall response rate, OS = overall survival, D = docetaxel, C = cisplatin, d = day 
 
2.4 
Rationale 
 
Phosphatidylinositol 3-kinase (PI3K) pathway activation contributes to both tumor resistance and 
disease progression in SCCHN [27] and is among the most frequently altered pathways in SCCHN 
tumors [28]. Moreover, pre-clinical data suggests that PI3K-γ/δ inhibition (avoiding direct 
cytotoxicity to normal B cells [29] can reduce regulatory T cells (Tregs) and myeloid-derived 
suppressor cells (MDSCs) in the TME which may enhance sensitivity of the tumor in the context of 
prior PD-1 inhibitor exposure [30]. In addition, inhibition of the PI3K pathway has been shown to 
lead to increased efficacy of the taxane microtubule inhibitor paclitaxel in ovarian cancer and 
malignant glioma cell lines [31] – supporting the rationale for combining PI3K targeted therapy with 
a taxane after immunotherapy exposure. 
 
Prior to the approval of 1L (chemo)immunotherapy in R/M SCCHN in 2019, the phase II BERIL-1 
study showed that median PFS and OS was superior (4.6 vs. 3.5, p=0.01; 10.4 vs. 6.5), and 
tolerability reasonable, with the use of the pan-PI3K inhibitor buparlisib vs. placebo when combined 
with paclitaxel among 2L, platinum-refractory patients [32]. The overall response rate was 39% vs. 
14% (p<0.01) favoring the buparlisib plus paclitaxel combination. Follow-up analyses showed that 
patients with TP53 alterations, HPV negative disease, and immune cell infiltration in their tumors 
had improved outcomes with the combination [33], the latter providing further support that exposure 

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after PD-1 blockade may be beneficial. 
 
We propose a novel clinical trial to evaluate the combination of the PI3K-γ/δ inhibitor duvelisib in 
combination with taxane therapy (docetaxel) for the treatment of R/M, incurable SCCHN patients 
who previously received PD-1 inhibitor-based therapy in the 1L. We hypothesize that utilizing 2L 
PI3K pathway inhibition with taxane therapy after immunotherapy exposure will yield an overall 
response rate approaching 30%. 
 
2.5 
Correlative Studies Background 
 
Alterations leading to activation of the PI3K pathway include gain-of-function mutations and 
amplifications in PIK3CA, PTEN alterations (such as loss of heterozygosity, inactivating mutations, 
or loss of expression), as well as overexpression or activation of downstream or upstream signaling 
molecules. While PIK3CA mutations (15%–20%) and reduced PTEN activity (identified in 6% to 
82% of patients) are the most frequently reported molecular alterations of the PI3K pathway in 
SCCHN, overexpression of the upstream EGFR (occurring in about 90% of patients) is also 
expected to lead to PI3K pathway activation [34]. Additionally, activation of the PI3K pathway is 
likely to affect the response of SCCHN to taxanes such as paclitaxel, as PI3K activation was shown 
to contribute to paclitaxel resistance in other tumor types [35-37]. Further, inhibition of the PI3K 
pathway led to an increased efficacy of paclitaxel (a taxane) in ovarian cancer and malignant glioma 
cell lines [31]. These observations, together with the reported activity of the PI3K inhibitor 
buparlisib in SCCHN further support the key role of PI3K pathway in SCCHN. 
Several other molecular alterations are frequently reported in SCCHN, including TP53 mutation 
(40%–75%), or amplification (10%–30%), and CDKN2A (p14/ARF) inactivation (75%). TP53 
mutations are known to be associated with a poor prognosis, as patients with TP53-altered tumors 
have decreased postsurgical survival [38]. Various publications have also reported an association 
between TP53 mutational status and response to platinum-based therapy in SCCHN. While some 
have reported that TP53 mutations may predict improved SCCHN cell response to cisplatin, or that 
TP53-mutant ovarian tumors were sensitive to taxane-platinum–based chemotherapy, other 
publications showed that functional or high-risk TP53 mutations were associated with resistance to 
cisplatin-based therapies [39, 40]. These observations highlight the importance of understanding the 
p53 cellular networks and their relation to responses to therapy. 
Infection with the human papillomavirus (HPV), occurring in up to approximately 44% of cases, has 
been shown to contribute to SCCHN etiology and to influence outcomes [41]. HPV-negative 
SCCHN tumors differ markedly from HPV-positive SCCHN in their clinical, immunological, and 
molecular characteristics – and have an overall worse prognosis. In addition, a strong association has 
been reported between TP53 alterations and HPV-negative SCCHN [34, 42]. 
The importance of immune markers in predicting outcome in SCCHN has been highlighted in recent 
studies. Infiltration of immune cells, especially CD8+ cells, was previously shown to be associated 
with an improved response to chemoradiotherapy [43]. In addition, data suggest that expression of 
the programmed cell death ligand-1 (PD-L1) correlates with an improved clinical outcome under 
treatment with programmed cell death receptor-1 (PD-1) inhibitors [44]. Mutational load, identified 
by the total number of mutations present in a tumor specimen, is a potential biomarker for response 

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to immunotherapy, as highly mutated tumors are more likely to harbor neoantigens, which make 
them targets of activated immune cells [45]. These data highlight the potential of immune markers 
and mutational load as prognostic and predictive markers in SCCHN and warrant further 
exploration. 
 
Follow-up analyses from the BERIL-1 study 
comparing either buparlisib or placebo with 
paclitaxel in R/M SCCHN has provided some 
insight in regards to meaningful biomarker 
findings in this setting [33]. They characterized 
frequencies of molecular alterations and found 
PI3K pathway activation in 13.8-16.1% of 
patients; with 76-85% of their study population 
being HPV-negative. TP53 was altered in 58-67% 
of HPV-negative paricipants compared with 34- 
42% among the HPV-positive subgroup. A higher 
frequency of TP53 alterations and a lower frequency of PIK3CA alterations was noted in the HPV- 
negative group. When accounting for differences in survival based on PI3K pathway activation  
status in the BERIL-1 study, there was no difference between the buparlisib and placebo arms. A 
trend towards improved PFS and ORR was noted with buparlisib use, however (Figure panel A). Of 
interest, patients with tumors having HPV-negative status, TP53 alterations or low mutational load 
derived clinical benefit with the combination of buparlisib and paclitaxel. 
 
A potential relationship between PD-L1 expression and treatment benefit was explored, using the 
1% expression cutoff previously described in the 
literature. An improved OS benefit with the 
combination of buparlisib and paclitaxel was 
observed in patients showing immune cell 
infiltration, regardless of the compartment where 
this infiltration occurred. OS benefit with this 
combination was increased in patients with the 
presence 
of 
intratumoral 
tumor 
infiltrating 
lymphocytes (TILs) ≥10% [HR = 0.51 (95% CI, 
0.26–1.00)] (Figure panel B), stromal TILs ≥15% 
[HR = 0.53, (95% CI, 0.33–0.85)], intratumoral 
CD8-positive cells ≥5% [HR = 0.45 (95% CI, 
0.23–0.86)], stromal CD8-positive cells ≥10% 
[HR = 0.47, (95% CI, 0.28–0.79)] or CD8-positive 
cells in invasive margins >25% [HR = 0.37 (95% CI, 0.14–0.94)]. There was, however, no clear 
relationship between the molecular alterations noted above and the markers of immune infiltration – 
understanding samples sizes in some subgroups were limited. 
 
While these preliminary biomarker findings are important, further investigation is warranted to 
understand how prior anti-PD-1 therapy impacts these molecular associations and immunologic 
parameters, which will be an important part of the exploratory correlative analysis of the present 
study. 

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3. PARTICIPANT SELECTION 
 
3.1 
Eligibility Criteria 
 
Participants must meet the following criteria on screening examination to be eligible to participate in 
the study: 
 
1. Participants must have histologically confirmed squamous cell carcinoma of the head and 
neck (SCCHN) with evidence of recurrent, metastatic (R/M) or advanced, incurable disease 
from any mucosal subsite including oral cavity, oropharynx, larynx, hypopharynx, nasal 
cavity, and the paranasal sinuses. 
2. Participants must have at least one RECIST v1.1 measurable lesion, as defined as at least one 
lesion that can be accurately measured in at least one dimension (longest diameter to be 
recorded for non-nodal lesions and short axis for nodal lesions) 1 cm with CT scans or MR 
imaging. 
3. Must have had at least 1, but no more than 2, prior lines of prior systemic therapy for R/M 
SCCHN; one of these lines should have included PD-1/L1 blockade 
a. Platinum-based therapy as part of definitive/adjuvant or curative-intent treatment can 
count as 1 prior line of therapy if the subject progressed within 6 months of receiving 
therapy. 
b. At least 2 weeks must have elapsed since the end of prior chemotherapy, biological 
agents (3 weeks for anti-cancer monoclonal antibody containing regimens) or any 
investigational drug product, with adequate recovery of treatment-related toxicity to 
NCI CTCAE Version 5.0 grade ≤1 (or tolerable grade 2) or back to baseline (except 
for alopecia or peripheral neuropathy). 
4. Be ≥18 years of age on the day of signing informed consent. 
5. Must provide prior data on tumor PD-L1 expression status and HPV status, if available 
6. Have a performance status of 0 or 1 on the ECOG Performance Scale (see Appendix A). 
7. Participants must have adequate organ and marrow function as defined below (within 14 
days prior to study registration): 
− 
absolute neutrophil count 
≥ 1,000/mcL 
− 
hemoglobin 
≥ 9 g/dL 
− 
platelets 
≥ 100,000/mcL 
− 
total bilirubin 
≤ upper limit of normal (ULN) 
− 
AST(SGOT)/ALT(SGPT) 
≤ 2.5x institutional ULN (or ≤ 1.5x institutional ULN if 
concomitant with alkaline phosphatase >2.5x institutional ULN) or ≤ 5x ULN for those 
with liver metastases 
− 
serum creatinine 
≤ 1.5x ULN 
OR 
− 
creatinine clearance 
≥ 60 mL/min/1.73 m2 for participants with creatinine levels 
above 1.5x ULN 

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− 
coagulation profile 
INR ≤ 1.5x ULN unless the participant is receiving an 
anticoagulant 
8. Baseline tumor measurements must be documented from imaging within 28 days prior to 
study registration. 
9. Female subjects of childbearing potential should have a negative urine or serum pregnancy 
test within 7 days of study registration. Female subjects of childbearing potential should have 
a negative urine or serum pregnancy test repeated within 72 hours prior to receiving the first 
dose of study medication. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
10. Female and male subjects of childbearing potential must agree to use an adequate method of 
contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, 
for the duration of study participation, and 4 months after completion of stud drug 
administration. Contraception is required before starting the first dose of study medication 
through 120 days after the last dose of study medication. Note: Abstinence is acceptable if 
this is the usual lifestyle and preferred contraception for the subject. 
11. Be willing and able to provide written informed consent for the trial. 
3.2 
Exclusion Criteria 
 
Participants who exhibit any of the following conditions at screening will not be eligible for 
admission into the study. 
 
1. Have been previously treated with 3 or more lines of systemic therapy for R/M SCCHN. 
a. Have received treatment with a prior PI3K pathway inhibitor 
2. Have received radiation therapy (RT) within 14 days of the first dose of duvelisib on study. 
3. Participant has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided they 
are stable (without evidence of progression by imaging and off systemic steroids for at least 
4 weeks prior to the first dose of study treatment), and have no evidence of new or enlarging 
brain metastases. This exception does not include carcinomatous meningitis which is 
excluded regardless of clinical stability, because of the poor prognosis and progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other adverse 
events. 
4. Concurrent administration of other cancer specific therapy or investigational agents during 
the course of this study. 
5. Uncontrolled intercurrent illness including but not limited to ongoing or active infection; 
evidence of symptomatic congestive heart failure, unstable angina pectoris, stroke, or 
ventricular arrhythmia within 6 months of enrollment. 
6. Have received a live or live attenuated vaccine within 4 weeks of the first dose of duvelisib. 
7. Have received medications or consumed foods that are strong inhibitors or inducers of 
cytochrome P450 (CYP3A) within 2 weeks of, or while on, duvelisib. 

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8. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions might include basal cell carcinoma of the skin or squamous cell carcinoma of the 
skin that has undergone potentially curative therapy or in situ cervical cancer. 
9. Known human immunodeficiency virus (HIV) carrier. Any known positive test result for 
hepatitis B virus or hepatitis C virus indicating presence of virus, e.g., hepatitis B surface 
antigen (HBsAg, Australia antigen) positive, or hepatitis C antibody (anti-HCV) positive 
(except if HCV-RNA negative). 
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator. 
11. Subjects who are pregnant, or breastfeeding, or expecting to conceive or father children 
within the projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. Breastfeeding should be discontinued 
if the mother is treated on this protocol. Women who could potentially become pregnant 
while undergoing treatment on this protocol must be willing to use 2 methods of 
contraception. 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. Women, minorities and 
other underrepresented populations are all at risk to develop head and neck cancers. 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol-specific therapy and/or intervention. Issues 
that would cause treatment delays should be discussed with the Principal Investigator (PI) of the 
registering site. If the subject does not receive protocol therapy following registration, the subject 
must be taken off study in the CTMS (OnCore) with an appropriate date and reason entered. 
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP#: REGIST-101) must be followed. 

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4.3 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at the DFCI by the Study Coordinator. All 
sites should call the Study Coordinator 
 to verify registration. Following registration, 
participants should begin protocol therapy within 5 days. Issues that would cause treatment delays 
should be discussed with the Sponsor-Investigator. If the subject does not receive protocol therapy 
following registration, the subject must be taken off study in the CTMS (OnCore) with an 
appropriate date and reason entered. 
4.4 
Registration Process for Other Investigative Sites 
 
To register a participant, the following documents should be completed by the participating site and 
faxed 
or e-mailed to the Study Coordinator: 
• Signed participant consent form 
• HIPAA authorization form 
• Completed eligibility checklist 
The participating site will then call or e-mail the Study Coordinator to verify eligibility. The Study 
Coordinator will follow DF/HCC policy (REGIST-101) and register the participant on the protocol. 
The Study Coordinator will fax or e-mail the participant study number to the participating site. The 
Study Coordinator will also contact the participating site and verbally confirm registration. 
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the participant's malignancy. 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential risks 
are described in Section 7. Appropriate dose modifications are described in Section 6. 
 
Safety Run-In: The first N=3 subjects to enroll to the study will be part of a safety run-in to ensure 
adequate safety in combining duvelisib with docetaxel and monitor for drug interactions between the 
two study agents -- given the potential for overlapping toxicities. Those participants in the safety 
run-in will receive the lead-in phase of duvelisib as outlined below (25 mg orally twice daily for 7 ± 
2 days) prior to initiation of docetaxel. Following the lead-in phase, in cycle 1 of duvelisib they will 
receive docetaxel at 56 mg/m2 intravenously (IV) (prespecified dose level -1) on a 21-day cycle and 
continue that dose in subsequent cycles (there is no escalation of the docetaxel dose on study for 
these patients). Toxicity management should follow guidelines in Section 6.1. If >1 subject in the 
safety run-in has an unacceptable toxicity (see Section 6.4) then study accrual will pause for review 
by the overall PI and drug sponsor; otherwise, enrollment may proceed using the 75 mg/m2 of 
docetaxel outlined below for all subsequent patients. 
 
Lead-In Phase: For the first cycle only, patients will receive duvelisib 25 mg orally twice daily for 7 
± 2 days (1 week) prior to the initiation of docetaxel chemotherapy. Duvelisib may be administered 

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without regard to meals; however, subjects should avoid grapefruit and grapefruit juice while on 
duvelisib. Duvelisib capsules should be swallowed whole with a glass of water. Patients are advised 
not to open, break, or chew the capsules. 
 
Following the lead-in phase, patients will continue onto cycle 1 of duvelisib at the same dose of 25 
mg orally twice daily on days 1 through 21. Docetaxel will be administered intravenously (IV) at a 
dose of 75 mg/m2 on day 1 of a 21-day cycle (in all remaining participants after the N=3 patients 
start the safety run-in) until disease progression or unacceptable toxicity. Treatment duration is 
planned for 24 months (or longer if patient exhibits good tolerance and clinical benefit), unless 
unacceptable toxicity, disease progression, or withdrawl of consent occurs. Following the first 21- 
day cycle of therapy, both duvelisib and docetaxel are to be continued concurrently in 21-day 
subsequent cycles. 
 
Duvelisib compliance will be monitored as part of the study. Each participant will be required to 
maintain a medication diary of each dose of medication. The medication diary will be returned to the 
clinic study staff at the end of each 21-day cycle. 
 
With docetaxel chemotherapy, granulocyte-colony stimulating factor (GCSF) support can be 
administered (at the treating physician’s discretion). For pegfilgrastim, 6 mg subcutaneosly should 
be administered once, at least 24 hours and no later than 72 hours after completion of the docetaxel 
infusion. Alternatively, tbo-filgrastim can be administered once per day at a dose of 300 or 480 
mcg(based on patient weight) at least 24 hours after the completion of the docetaxel infusion and no 
later than 72 hours after completion of the docetaxel infusion. Tbo-filgastrim should be administered 
dailyfor at least 5 days and continued for a maximum of 14 days, or until the ANC is >1000. Tbo- 
filgrastim should not be administered with 24 hours of the start of the next cycle of docetaxel. 
 
Standard 
pre-medications 
including 
dexamethasone, 
palonosetron 
or 
ondansetron, 
and 
(fos)aprepitant are permitted for anti-emetic effect. Pre-medication with dexamethasone prior to 
taxane exposure is strongly encouraged for all participants. 
 
In addition to the continuous routine toxicity monitoring by the study team throughout the duration 
of the trial, the following stopping rule will be used to monitor excessive protocol treatment related 
toxicity/delays (as noted in Sectio 6.4): if 3 or more of the first 10 patients (which includes the 3 
patients treated as part of the safety run-in) who begin protocol treatment experience treatment 
related toxicities, accrual to the trial will be suspended to further evaluate the events and decisions 
made regarding the overall status of the trial. Adverse events will be continuously monitored 
throughout the trial by the study team with decisions made accordingly regarding the study status 
and patient entry throughout the duration of the trial. 
 
5.2 
Pre-Treatment Criteria 

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5.2.1 
Cycle 1, Day 1 
Eligibility and exclusion criteria are provided in Section 3. These criteria will be assessed within 28 
days of the first day of study treatment to establish eligibility and baseline values. Informed consent 
will be obtained after the study has been fully explained to the subject and before the conduct of any 
screening procedures or assessments. If screening assessments occur within 3 days before start of 
study treatment, then they may serve as the baseline Cycle 1 Day 1 visit, and Cycle 1 Day 1 labs do 
not need to be performed. Cycle 1 Day 1 labs do not need to re-meet eligibility criteria. 
 
Demographic information and baseline characteristics will be collected at the Screening Visit. 
Standard demographic parameters include age, sex, and race/ethnicity (recorded in accordance with 
prevailing regulations). Baseline characteristics will include ECOG performance status (Appendix 
A), disease status, medical histories, and prior and concomitant medications. 
 
Additional testing required, as per Section 10, includes: hematology panel (see Table 2), chemistry 
panel, coagulation panel, urine or serum HCG (in women of childbearing potential; see Section 3 for 
when serum HCG testing is required), and an ECG. 
 
Table 2. Clinical Laboratory Testing 
 
Category 
Test 
Hematology panel 
Hematocrit, hemoglobin, platelet count, white cell count with 
differential (bands, basophils, eosinophils, lymphocytes, 
monocytes, neutrophils), absolute neutrophil count 
Chemistry panel 
Chloride, potassium, sodium, BUN, serum creatinine, 
phosphorus, calcium, albumin, total protein, alkaline 
phosphatase, ALT, AST, total bilirubin (Note: the frequency of 
checking magnesium levels is at the discretion of the treating 
provider) 
Coagulation profile 
PT/INR and aPTT 
Thyroid function tests 
TSH and free T4 if indicated with prior head and neck 
radiation exposure 
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; PT = 
prothrombin time/INR = international normalized ratio; aPTT = partial thromboplastin time; TSH = thyroid stimulating 
hormone 
 
 
A fresh tumor biopsy sample is preferred but not required prior to the start of duvelisib and 
docetaxel, so as to garner the most recent possible information about PD-L1 status and other 
biomarkers. If obtaining a fresh biopsy is unfeasible or carries an unacceptable risk/benefit profile, 
an archival tissue sample must be available for histologic confirmation of SCCHN. 
 
5.2.2 
Subsequent Cycles 
 
Reasonable effort should be made to conduct study visits on the day scheduled ( 3 days). 
 
Any changes from screening clinical evaluation findings that meet the definition of an adverse event 
(AE) will be recorded on the AE page of the eCRF. 
 
The participants ECOG performance status, weight (in kilograms), vital signs, interval history since 
the last visit, and physical examination are performed at each study visit. Concomitant medications 

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should also be reviewed at each study visit. In addition, the adverse event (AE) grid should be 
completed at each study visit. All laboratory values should be reviewed before proceeding with an 
additional cycle of treatment. Participants will undergo every-21 day or every 3-week assessments 
while on study (which coincides with the start of each cycle of therapy). The drug diary for the prior 
cycle should be reviewed at each study visit by the clinical staff. 
 
5.2.3 
Additional On-treatment Assessments 
 
Tumor Assessments: 
 
Tumor assessments will be performed according to RECIST v1.1 (see Section 11), at baseline and 
with response evaluations performed every 9 weeks (every 3 cycles), or as clinically indicated. In the 
case of response, confirmatory scans are recommended at least 4 weeks after initial response and 
every 9 weeks after the scan that documented the initial response. In the case of progressive disease, 
confirmatory scans are not required and are at the discretion of the treating investigator. 
 
Continued treatment after initial progression is permitted, provided the patient is thought to be 
deriving clinical benefit and is counseled regarding the risks and benefits of continued treatment. 
This decision should be made in discussion with the overall study PI. If progression is confirmed, the 
date of progression is dated as the time of the original scans for study monitoring purposes. 
 
On-Treatment Tumor Biopsy Collections: 
 
An on-treatment tumor tissue biopsy will be offered at the end of cycle 2 (around week 6) but before 
cycle 3 (around week 9) in a subset of patients who are willing and able to undergo tissue sampling. 
Details about collection and handling of the tumor biopsy specimen can be found in Sections 9 and 
10. 
 
5.2.4 
End-of-treatment Procedures 
 
All subjects will be asked to return to the site for a final, end-of-treatment visit (EOT). This visit 
must be performed within 30 days of final administration of study treatment. EOT assessments will 
not have to be repeated if the same assessments were performed within 7 days of this planned visit. 
The subject will be followed for 30 days after the last study intervention (duvelisib or docetaxel) for 
adverse events. 
 
The reason for the study participant coming off therapy should be clearly documented. For any 
reason other than for progression of disease, tumor assessments should be performed every 8-12 
weeks if a patient comes off the study drug within 1 year of enrollment (but ultimately at the 
discretion of the treating investigator). 
 
The participants ECOG performance status, weight (in kilograms), vital signs, interval history since 
the last visit, and physical examination are performed at the end-of-treatment visit. Concomitant 
medications should also be reviewed at this visit. In addition, the adverse event (AE) grid should be 
completed at this visit. 

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5.3 
Chemotherapy and Targeted Therapy Administration 
 
5.3.1 
Docetaxel 
 
On the day of docetaxel administration, the drug will be administered per standard institutional 
guidelines followed by a 30 minute wait period at the end of the infusion, to evaluate for an infusion 
reaction. On the day of docetaxel administration, the morning dose of duvelisib should be given at 
least 30 minutes prior to starting the docetaxel, and the evening dose of duvelisib should occur at 
least 1 hour after the completion of the infusion of docetaxel. For docetaxel, standard operating 
procedure should be applied when recalculating weight-based dosing at the beginning of each cycle. 
Additional intravenous hydration is not required at study visits, but is at the discretion of the treating 
investigator. Pre-medication with dexamethasone prior to taxane exposure is strongly encouraged for 
all participants. 
 
5.3.2 
Duvelisib 
 
Duvelisib capsules should be swallowed whole with a glass of water (approximately 8 ounces). 
Advise patients not to open, break, or chew the capsules. Duvelisib may be administered without 
regard to meals; however, subjects should avoid grapefruit and grapefruit juice while on duvelisib. 
 
5.4 
General Concomitant Medication and Supportive Care Guidelines 
 
5.4.1 
Concomitant Medication Guidelines 
 
The following medications are prohibited during the study (unless utilized to treat a drug-related 
adverse event): 
• Immunosuppressive agents 
• Immunosuppressive doses of systemic corticosteroids with the exception of pre-medication 
and anti-emetic purposes 
• Any concurrent anti-neoplastic therapy (i.e., chemotherapy, hormonal therapy, 
immunotherapy, extensive, non-palliative radiation therapy, or standard or investigational 
agents) 
 
Prohibited Concomitant Therapy 
Guidance 
Use of Vaccines 
For all subjects, the use of live or live attenuated vaccines 
is prohibited during the treatment with either study 
intervention. The use of inactivated (or killed) vaccines 
(such as pneumococcal pneumonia vaccine) is allowed 
during the study. 
Immunosuppressants 
Subjects are not to receive ongoing treatment with chronic 
immunosuppressants (e.g., cyclosporine) or systemic 
steroids for >1 week at doses higher than the equivalent of 
20 mg prednisone once daily. 
Medications or Foods that Strongly Inhibit or Induce 
CYP3A4 
Use of a strong CYP3A inhibitor or inducer during 
treatment with duvelisib is prohibited. Co-administration 
with a strong CYP3A inhibitor increases duvelisib 
exposure, which may increase the risk of duvelisib 
toxicities. Co-administration with a strong CYP3A inducer 
decreases duvelisib exposure, which may reduce duvelisib 

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efficacy. See Table below. 
Medications that are Substrates of CYP3A 
Co-administration with duvelisib decreases AUC of a 
sensitive CYP3A4 substrate which may decrease the 
efficacy of these drugs. Consider finding an alternative 
drug that is not a substrate of CYP3A4. See Table below. 
 
 
5.4.2 
Recommended Prophylaxis 
 
Based on the duvelisib clinical experience to date, the following are recommended: 
• Subjects are required to receive pneumocystis prophylaxis concomitant with duvelisib 
treatment per institutional guidelines. After completion/discontinuation of duvelisib 
treatment, continue prophylaxis until the absolute CD4+ T-cell count is greater than 200 
cells/μL. 
• HSV and VZV infections have been observed with duvelisib; therefore, herpes (HSV/VZV) 
prophylaxis concomitant with treatment is recommended, per treating investigator discretion 
according to institutional guidelines. 
• Subjects with a history of CMV infection/reactivation or viremia should be monitored for 
reactivation by polymerase chain reaction (PCR) or antigen test at least monthly. 
Prophylactic treatment per institutional guidelines is recommended for subjects considered 
by Investigators to be at high risk for CMV reactivation. 
• Antimicrobial prophylaxis and pneumococcal pneumonia vaccine are recommended for 
subjects with history of or considered at high risk for infections and during periods of severe 

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neutropenia. Choice of antimicrobial agent (antifungal, antibiotic, antiviral) is per treating 
investigator discretion, but the restrictions on the use of CYP3A inducers, inhibitors, and 
substrates should be considered. 
 
5.4.3 
Supportive Care Guidelines 
 
The following treatments are permitted throughout the duration of the study treatment phase and 
during follow-up: 
 
• Standard therapies for pre-existing medical conditions unless listed as prohibited therapy 
below. Any medication intended solely for supportive care (e.g., analgesics, anti-diarrheal, 
anti-depressants) may be used at the investigator’s discretion. At the discretion of the 
investigator, prophylactic antiemetic and anti-diarrheal medication(s) may be used as per 
standard clinical practice before subsequent doses of study drugs. 
• Anticoagulants: anticoagulation with heparin, heparin derivatives, and/or warfarin may be 
given at the discretion of the treating physician. Coagulation parameters should be checked at 
each cycle, or more frequently at the discretion of the treating physician. 
• Pain medications administered per standard clinical practice are acceptable while the patient 
is enrolled in the study. 
 
Patients who experience toxicities should be treated symptomatically as clinically indicated. 
Medications that are considered necessary for the subject’s welfare and that are not expected to 
interfere with the evaluation of study treatment or be restricted may be given at the discretion of the 
investigator. Ancillary treatments will be given as medically indicated. 
 
5.5 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue until 
one of the following criteria applies: 
• 
Disease progression 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Unacceptable adverse event(s), see Section 6.0 
• 
Participant demonstrates an inability or unwillingness to comply with study requirements 
and/or activities, including the oral medication regimen and/or documentation 
requirements 
• 
Participant decides to withdraw from the protocol therapy 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
• 
Pregnancy 
Participants will be removed from the protocol therapy when any of these criteria apply (discussion 
with the PI is encouraged in this scenario). The reason for removal from protocol therapy, and the 
date the participant was removed, must be documented in the case report form (CRF). Alternative 
care options will be discussed with the participant. 

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When a participant is removed from protocol therapy and/or is off of the study, the participant’s 
status must be updated in OnCore in accordance with REGIST-OP-1. . 
 
5.6 
Duration of Follow-Up 
 
Participants will be followed for best overall response and development and documentation of first 
disease progression and for survival throughout the course of the trial for 3 years from the time of 
study registration. Participants removed from protocol therapy for unacceptable adverse event(s) 
who have not developed first disease progression at the time of discontinuation of protocol therapy, 
will continue to be followed for disease progression. All participants enrolled will be followed for 
survival (until death or 3 years from study registration,whichever occurs first). All adverse events 
leading to treatment discontinuation will be followed as appropriate until resolution or stabilization. 
5.7 
Criteria for Taking a Participant Off Study 
 
Participants will also be removed from study when any of the following criteria apply: 
• Patient completed required follow-up 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. In addition, the study team will ensure Off Treatment/Off Study information is updated 
in OnCore in accordance with DF/HCC policy REGIST-101. 
 
In the event of unusual or life-threatening complications, participating investigators must 
immediately notify the Principal Investigator, Glenn J. Hanna, MD, at DFCI/Partners pager 46231. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Dose delays and modifications will be made as indicated below. The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for dose delays and dose modifications. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP website: 
 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
If possible, symptoms should be managed prophylactically and/or supportively. In the case of 
toxicity, appropriate medical treatment should be used (including anti-emetics, anti-diarrheals, etc.). 
 
All adverse events experienced by participants will be collected from the time of the first dose of 
study treatment, through the study and within 30 days of the last study intervention. Participants 
continuing to experience toxicity at the last scheduled study visit may be kept on the study until the 
toxicity has resolved, or until the toxicity is deemed irreversible. 

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If one of the study two drugs is delayed due to drug related toxicities during a treatment cycle, the 
other study drugs in the regimen may be administered at the discretion of the investigator; when 
dosing is resumed, dose reduction should only be applied to the study drug that was withheld. 
Missed days or cycles of either drug can be made up, at the discretion of the treating investigator. 
 
6.1 
Duvelisib 
 
The dose level of duvelisib may be modified to manage duvelisib toxicities or overlapping toxicities 
in combination with docetaxel. Non-hematologic and hematologic adverse events (AEs) for 
duvelisib for non-overlapping toxicities in combination with docetaxel should be managed with 
supportive care, treatment hold, dose reduction, or discontinuation of duvelisib as described below. 
Additional information regarding management of duvelisib toxicities can be found in the Summary 
of Data and Guidance to the Investigator section of the duvelisib investigator brochure (IB). 
Refer to Table 3 for dose level modifications recommended for duvelisib (this applies to patients in 
the safety run-in). Subjects who have a duvelisib dose reduction due to a toxicity will not be eligible 
for a dose re-escalation. Any subject who develops an unacceptable toxicity at the 15 mg BID 
dosage of duvelisib should discontinue duvelisib but can continue docetaxel on study at the 
discretion of the treating investigator. 
If a dose is missed or vomited up by fewer than 6 hours, the patient should take the missed dose right 
away and take the next dose as usual. If a dose is missed or vomited up by more than 6 hours, advise 
patients to wait and take the next dose at the usual time. 
Provide prophylaxis for Pneumocystis jirovecii (PJP) during treatment with duvelisib. Following 
completion of treatment, continue PJP prophylaxis until the absolute CD4+ T cell count is greater 
than 200 cells/µL. Withhold duvelisib in patients with suspected PJP of any grade, and discontinue if 
PJP is confirmed. Consider prophylactic antivirals during duvelisib treatment to prevent 
cytomegalovirus (CMV) infection including CMV reactivation. 
Duvelisib may be held up to 42 days due to toxicity. While duvelisib is being held, the subject may 
continue to receive docetaxel at the discretion of the treating investigator. Doses held for >42 days 
due to treatment-related toxicity will result in permanent discontinuation of duvelisib. 
Table 3. Duvelisib Dose Level Modifications for Toxicity 
Dose Level 
Duvelisib 
Starting Dose 
25 mg by mouth twice daily 
Dose Level -1 
15 mg by mouth twice daily 
Subsequent Dose Modification 
Discontinue duvelisib if patient is unable to tolerate 
15 mg twice daily 
 
Table 4. Recommended Duvelisib Dose Modifications for the Management of Duvelisib Toxicities 
Toxicity 
Adverse Reaction Grade 
Dose Modification and Recommended 
Management 
Non-hematologic AEs 
Infections 
Grade 3 or higher 
Withhold duvelisib until resolved. Resume 
at the same or reduced dose 
Clinical CMV infection or viremia 
(positive PCR or antigen test) 
Withhold duvelisib until resolved. Resume 
at the same or reduced dose. If duvelisib is 

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resumed, monitor subjects for CMV 
reactivation (by PCR or antigen test) at 
least monthly 
PJP 
For suspected PJP, withhold duvelisib 
until evaluated. For confirmed PJP, 
discontinue duvelisib 
Non-infectious diarrhea or 
colitis 
Mild/moderate diarrhea 
(Grade 1-2, up to 6 stools per 
day over baseline) and 
responsive to antidiarrheal 
agents, 
OR 
Asymptomatic (Grade 1) 
colitis 
No change in dose 
• Initiate supportive therapy with 
antidiarrheal agents 
as appropriate 
• Monitor at least weekly until resolved 
Mild/moderate diarrhea 
(Grade 1-2, up to 6 stools per 
day over baseline) and 
unresponsive to antidiarrheal 
agents 
Withhold duvelisib until resolved 
• Initiate supportive therapy with enteric 
acting 
steroids (e.g., budesonide) 
• Monitor at least weekly until resolved 
• Resume at a reduced dose (see Table 3) 
Abdominal pain, stool with 
mucus or blood, change in 
bowel habits, peritoneal 
signs, 
OR 
Severe diarrhea (Grade 3, >6 
stools per day over baseline) 
Withhold duvelisib until resolved 
• Initiate supportive therapy with enteric 
acting 
steroids (e.g., budesonide) or systemic 
steroids 
• Monitor at least weekly until resolved 
• Resume at a reduced dose (see Table 3) 
• For recurrent Grade 3 diarrhea or 
recurrent colitis of any grade, discontinue 
duvelisib 
Life-threatening 
Discontinue duvelisib 
Cutaneous reactions 
Grade 1-2 
No change in dose 
• Initiate supportive care with emollients, 
antihistamines (for pruritus), or topical 
steroids 
• Monitor closely 
Grade 3 
Withhold duvelisib until resolved 
• Initiate supportive care with emollients, 
antihistamines (for pruritus), or topical 
steroids 
• Monitor at least weekly until resolved 
• Resume at reduced dose (see Table 3) 
• If severe cutaneous reaction does not 
improve, worsens, or recurs, discontinue 
duvelisib 
Life-threatening 
Discontinue duvelisib 
SJS, TEN, DRESS (any grade) 
Discontinue duvelisib 
Pneumonitis without 
suspected infectious 
cause 
Moderate (Grade 2) 
symptomatic pneumonitis 
Withhold duvelisib 
• Treat with systemic steroid therapy 
• If pneumonitis recovers to Grade 0 or 1, 
duvelisib may be resumed at reduced dose 
(see Table 3) 
• If non-infectious pneumonitis recurs or 
patient does not respond to steroid therapy, 
discontinue duvelisib 

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Severe (Grade 3) or lifethreatening 
pneumonitis 
Discontinue duvelisib 
• Treat with systemic steroid therapy 
ALT/AST elevation 
3 to 5 × upper limit of 
normal (ULN) (Grade 2); >3 to 5x 
baseline if baseline was abnormal 
Maintain duvelisib dose 
• Monitor at least weekly until return to 
< 3 × ULN 
> 5 to 20 × ULN (Grade 3); >5 to 20x 
baseline if baseline was abnormal 
• Withhold duvelisib and monitor at least 
weekly until return to < 3 × ULN 
• Resume duvelisib at same dose (first 
occurrence) or at a reduced dose for 
subsequent occurrence (see Table 3) 
> 20 × ULN (Grade 4); >20x if 
baseline was abnormal 
Discontinue duvelisib 
Other Grade 3 Toxicities Attributed to Duvelisib 
Withhold duvelisib until resolved 
• Resume at a reduced dose (see Table 3) 
Hematologic AEs 
Febrile neutropenia 
Grade 3-4 
Interrupt duvelisib until afebrile and 
resolution of Grade 3 or Grade 4 
neutropenia to Grade ≤2 (ANC >1.0 Gi/L). 
Monitor ANC at least weekly until >1.0 
Gi/L. Resume at same dose (first 
occurrence) or at a reduced dose for 
subsequent occurrence 
Neutropenia 
ANC 0.5-1.0 Gi/L 
Maintain duvelisib dose. Monitor ANC at 
least weekly 
ANC <0.5 Gi/L 
Withhold duvelisib. Monitor ANC until 
>0.5 Gi/L. Resume duvelisib at same dose 
(first occurrence) or at a reduced dose for 
subsequent occurrence 
Thrombocytopenia 
Platelet count 25 to <50 Gi/L (grade 
3) with grade 1 bleeding 
No change in dose. Monitor platelet counts 
at least weekly 
Platelet count 25 to <50 Gi/L (grade 
3) with grade 2 bleeding or platelet 
count <25 Gi/L (grade 4) 
Withhold duvelisib. Monitor platelet 
counts until ≥25 Gi/L and 
resolution of bleeding (if applicable). 
Resume duvelisib at same dose (first 
occurrence) or resume at a reduced dose 
for subsequent occurrence 
Abbreviations: ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
CMV = cytomegalovirus; DRESS = drug reaction with eosinophilia and systemic systems; PCR = polymerase chain 
reaction; PJP = Pneumocystis jirovecii; pneumonia; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal 
necrolysis; ULN = upper limit of normal. 
 
6.2 
Docetaxel 
Dose modifications for the docetaxel component of the combined regimen are permitted and should 
follow institutional standards based on toxicity, with the following suggested modifications: 
 
A maximum of two dose reductions are permitted (or one dose reduction for patients in the safety 
run-in): if additional reductions are required, the docetaxel component of the regimen should be 
discontinued. Once a dose has been decreased, it should remain reduced for all subsequent dosing 
unless dose is further reduced. No dose (re-) escalations will be allowed. 
 
Docetaxel may be held up to 60 days due to toxicity. While docetaxel is being held, the subject may 
continue to receive duvelisib at the discretion of the treating investigator. Doses held for >60 days 

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due to treatment-related toxicity will result in permanent discontinuation of docetaxel unless 
discussed with the Sponsor-investigator. 
Recommended Dose Levels: 
Dose Level 
Docetaxel dose 
Starting dose* 
75 mg/m2 
Dose Level -1 
56 mg/m2 
Dose Level -2 
37 mg/m2 
* except for N=3 initial participants in the safety run-in (starting dose is at dose level -1) 
 
Recommended Dose Modifications for Toxicity: 
Toxicity 
Docetaxel 
Neutrophils (ANC) <500/mm3 lasting ≥5 days 
Decreased by -1 dose level 
Febrile neutropenia (body temperature ≥38.5C and ANC 
<1000/mm3) 
Decreased by -1 dose level 
Platelets <25,000/mm3 
Decreased by -1 dose level 
Platelets <50,000/mm3 with significant bleeding or 
requiring transfusion 
Decreased by -1 dose level 
Grade 4 hemoglobin (<6.5 g/100 mL) 
Decreased by -1 dose level 
Nausea or emesis ≥grade 3 despite optimal medical 
management 
Decreased by -1 dose level 
Stomatitis ≥grade 3 
Decreased by -1 dose level 
Diarrhea ≥grade 3 despite optimal medical management 
Decreased by -1 dose level 
Neuropathy (sensory or motor) grade 2 lasting >7 days or 
grade 3 lasting 7 days or less 
Decreased by -1 dose level 
Nephrotoxicity (creatinine clearance 50-59 mL/min or 
grade 3 creatinine elevation) 
No modification 
Total bilirubin >1.5x ULN 
No modification 
Total bilirubin >2.5x ULN 
75% of previous dose 
Total bilirubin >4x ULN 
50% of previous dose 
Other grade ≥3 toxicities (except fatigue or transient 
arthralgias, myalgias) 
Decreased by -1 dose level 
 
6.3 
Recommended Dose Modifications for the Management of Overlapping Toxicities for 
Duvelisib in Combination with Docetaxel 
 
Hematologic issues, non-infectious diarrhea or colitis, and hepatotoxicity are potential overlapping 
toxicities for duvelisib with docetaxel. In the event of overlapping toxicity while on combination 
therapy, the treating investigator may opt to hold one, or both, agents depending on the clinical 
suspicion for attribution to one or both agents. However, we recommend following the guidelines 
outined in Sections 6.1-6.2 for each respective agent in determing when to hold, for how long, and at 
what dose (if any) to resume. 
 
6.4 
Unacceptable Toxicity 
 
Unacceptable Toxicity Warranting Duvelisib and Docetaxel Discontinuation: 
• Any grade 4 adverse event will require permanent discontinuation with the following 
exceptions: 
− Grade 4 electrolyte abnormalities that are <72 hours in duration 
− Grade 4 neutropenia or lymphopenia which are <5 days in duration 
− For confirmed Pneumocystis jiroveci pneumonia (duvelisib discontinuation only) 

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The consideration to re-initiate study therapy under these exceptions will be made on a case by 
case basis after considering the overall benefit/risk profile and in consultation with the PI. 
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following 
list of reported and/or potential AEs and the characteristics of an observed AE will determine 
whether the event requires expedited reporting in addition to routine reporting. 
7.1 
Expected Toxicities 
 
Virtually all patients treated with duvelisib and/or docetaxel experience some drug-related toxicity, 
especially fatigue, some degree of cytopenias, limiting gastrointestinal toxicity (diarrhea or nausea 
and/or emesis). These adverse effects are seldom permanent or irreversible nor do they usually 
require interruption of therapy. 
 
Duvelisib 
Docetaxel 
>10% 
Edema 
Fatigue, headache 
Skin rash 
Hypophosphatemia, hyponatremia, hyperkalemia, 
hypoalbuminemia, hypocalcemia, weight loss 
Diarrhea, colitis, elevated serum lipase or amylase, nausea, 
abdominal pain, constipation, vomiting, mucositis, low 
appetite 
Neutropenia, anemia, thrombocytopenia, lymphocytosis 
Increased serum ALT or AST or alkaline phosphatase 
Sepsis, serious infection 
Musculoskeletal pain 
Renal insufficiency, increased creatinine 
Upper respiratory infection, pneumonia, dyspnea 
Fever 
>10% 
Skin reaction 
Fluid retention 
Diarrhea, nausea, stomatitis, vomiting 
Anemia, leukopenia, neutropenia, thrombocytopenia 
Increased alanine aminotransferase (ALT) and aspartate 
aminotransferase (AST) 
Infection 
Dysesthesia or paresthesia 
Asthenia, generalized weakness, myalgias 
Pulmonary disease 
Fever 
1-10% 
Skin reaction 
Cytolomegalovirus disease 
Arthralgias 
Pneumonitis or Pneumocystis jiroveci pneumonia 
1-10% 
Hypotension 
Dysgeusia 
Increased alkaline phosphatase, serum bilirubin 
Infusion site reaction 
Peripheral motor neuropathy 
Arthralgias 
<1% 
Onycholysis 
 
7.2 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade: The descriptions and grading scales found in 
the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 
will be utilized for AE reporting. All appropriate treatment areas should have access to a 
copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be downloaded from 
the CTEP web site: 

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http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
• For expedited reporting purposes only: 
AEs for the agent(s) that are listed above should be reported only if the adverse event varies 
in nature, intensity or frequency from the expected toxicity information which is provided. 
 
• Attribution of the AE should be documented with respect to each study treatment as 
follows: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 
Adverse Event Reporting 
 
7.3.1 In the event of an unanticipated problem or life-threatening complications treating 
investigators must immediately notify the PI. 
 
7.3.2 Investigators must report to the PI any adverse event (AE) that occurs after the initial dose of 
study treatment, during treatment, or within 30 days of the last dose of treatment on the local 
institutional SAE form. . 
 
7.3.3 
Serious Adverse Events 
 
7.3.3.1 
Definition 
 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe) 
• Requires inpatient hospitalization or causes prolongation of existing hospitalization (see note 
below) 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
• Is an important medical event (defined as a medical event(s) that may not be immediately life- 
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [e.g. medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) 
• Suspected transmission of an infectious agent (eg, pathogenic or non-pathogenic) via the study 
drug is an SAE. 

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Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not always 
serious by regulatory definition, these events must be handled as SAEs. 
 
Any component of a study endpoint that is considered related to study therapy should be reported as 
an SAE (e.g. death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
 
7.3.3.2 
Reporting SAEs 
 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol- 
specified procedures. All SAEs must be collected that occur within 100 days of discontinuation of 
dosing. All SAEs should be followed to resolution or stabilization. 
Investigators will be notified of all suspected, unexpected serious adverse reactions (SUSARs; 7-/15- 
Day Safety Reports) that occur during any clinical studies that are using duvelisib. Each site is 
responsible for notifying their IRB/IEC/Central Ethics Committee of these additional SUSARs in 
accordance with local regulations. 
7.3.3.3 
Overdose of Duvelisib 
 
For this study, overdose is defined as a daily dose of a study intervention higher than the prescribed 
daily dose. In the case of overdose, clinic staff should be notified immediately, and supportive care 
is to be given as indicated. Subjects should be informed to contact their doctor immediately if they 
have taken an overdose and should stop taking study interventions. Overdoses will not be considered 
SAEs unless the outcome of the overdose meets seriousness criteria as defined in Section 7.3.31. In 
the event of an overdose, the Sponsor should be notified within 24-hours. The subject should be 
carefully monitored for potential adverse reactions and symptomatic treatment instituted as per 
institutional practices. The study investigator will determine if and when dosing should resume. 
 
7.4 
DF/HCC Adverse Event Reporting Guidelines 
 
All participating sites will report AEs to the Sponsor-Investigator per DF/HCC requirements, and the 
IRB of record for each site as applicable per IRB policies. The table below indicates which events 
must be reported to the DF/HCC Sponsor-Investigator. 
 
Attribution 
DF/HCC Reportable Adverse Events(AEs) 
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected 
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
Not required 
5 calendar days 
5 calendar days# 
5 calendar days 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 

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7.5 
Reporting to the Food and Drug Administration (FDA) 
 
The Sponsor-Investigator will be responsible for all communications with the FDA. The Sponsor- 
Investigator will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.6 
Reporting to Hospital Risk Management 
 
Participating co-investigators will report to local Risk Management office any participant safety 
reports, sentinel events or unanticipated problems that require reporting per institutional policy. 
Secura Bio will be copied on all such reports in a timely fashion. 
 
 
7.7 
Reporting to the Secura Bio 
 
The Medical Monitors for this study may be contacted for advice or assistance. Contact details will 
be provided separately in a study contact list. Report SAEs to Secura Bio 
 
 
7.8 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the PI on the toxicity case 
report forms. AEs reported through expedited processes (e.g., reported to the IRB, FDA, etc.) must 
also be reported in routine study data submissions. Secura Bio will be copied on all such reports in a 
timely fashion. 
 
 
8. PHARMACEUTICAL INFORMATION 
 
8.1 
Study Agent: Duvelisib 
 
Devulisib; brand name: Copiktra® 
 
8.1.1 
Description 
 
Duvelisib is an oral PI3K inhibitor with dual inhibitory activity primarily against PI3K-δ and PI3K-γ 
which are expressed in hematologic malignancies. Inhibition of PI3K-δ reduced tumor cell 
proliferation while allowing survival of normal cells. Distribution: Vd: 28.5 L. Protein binding: 
>98%. Metabolism: Hepatic; primarily via CYP3A4. Bioavailability: 42%. Half-life elimination: 4.7 
hours. Time to peak: 1 to 2 hours. Excretion in feces: 79% (11% as unchanged drug) and urine: 14% 
(<1% as unchanged drug). 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, events must be reported within 1 business day of learning of the event. 

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8.1.2 
Form 
Duvelisib is available as a capsule in 15 and 25 mg doses. 
8.1.3 
Storage and Stability 
 
On receipt at the investigative site, duvelisib should remain in the packaging as provided until use or 
dispensation. The packaged product should be stored at the investigative site at 20 to 25°C (68 to 
77°F), with excursions permitted at 15 to 30°C (59 to 86°F). Temperature excursion procedures are 
provided in the IB (Section 4.6 or page 26). Expired drug is not to be dispensed. 
 
8.1.4 
Availability 
 
Duvelisib is commercially available (Copkitra), but will provided as investigational supply. 
 
8.1.5 
Administration 
 
Duvelisib will be administered by trained medical personnel at the investigational site. Treatment 
compliance will be monitored through documentation of study treatment administration in the 
subject’s medical record and via drug diary. Oral: administer with or without food. Swallow capsules 
whole; do not open, break or chew capsules. Provide PJP prophylaxis during treatment and continue 
until the absolute CD4+ T cell count is >200 cells/mL; consider prophylactic antivirals during 
treatment to prevent CMV infection and reactivation. It is acceptable for the on-site pharmacy to 
dispense the needed quantity of duvelisib in an amber prescription bottle. 
 
8.1.6 
Ordering 
 
 
 
 
 
8.1.7 
Accountability 
 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the duvelisib, using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form (See the NCI Investigator’s 
Handbook for Procedures for Drug Accountability and Storage). 
 
8.1.8 
Destruction and Return 
 
Unused and expired supplies of duvelisib will be destroyed on site per institutional standard practice. 
8.2 
Docetaxel 
 
Docetaxel will be commercially supplied. Docetaxel will be stored, prepared, and administered per 
standard of care/institutional standards. 

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9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
Background information on the pre-clinical and clinical rationale for these investigations is 
discussed in Section 2.5 above. 
 
As study participants carry a diagnosis of R/M SCCHN it is expected that most, if not all, will have 
undergone prior tumor biopsy sampling with tissue available for assessment of tumor PD-L1 CPS 
testing, tumor genomic sequencing with an available targeted in-house platform or commercially 
available assay (Foundation Medicine CDx, Guardiant360 CDx, Caris, etc.). If not previously 
completed prior to study enrollment, all subjects should have a biopsy of tumor tissue obtained 
subsequent to most recent prior anti-neoplastic therapy sent for tumor next-generation genomic 
sequencing and PD-L1 tumor testing (reported as CPS), if feasible. If this is not feasible or 
constitutes significant risk, tissue from archival reserves may be submitted. This would be  
considered standard of care for molecular and immune profiling in advanced head and neck cancer. 
The results of tumor molecular or gene and immune profiling will be used to determine PD-L1 
status, TP53 and PI3K pathway activation status, as well as HPV testing (if needed) for correlative 
analyses planned as part of the study. 
 
An on-treatment tumor tissue biopsy will be offered (as optional) to all participants on study with the 
expectation that roughly 50% of participants (N=15 subjects) would be willing and able to undergo 
re-biopsy. This will be offered at the end of cycle 2 (6 weeks) but before cycle 3 (9 weeks) if safe 
and feasible. Tumor tissue will be stored for later use to evaluate changes in gene and protein 
expression while on PI3K plus taxane therapy, and to assess changes in immunoprofiling metrics 
perhaps through digital spatial profiling (DSP) or multiplexed immunofluorescence (MIF) on FFPE 
tissue blocks or slides. 
 
9.1.1 
Collection and Handling of Specimens 
 
Ideally two core biopsies will be obtained at the time of all biopsy collections: cores should be 
placed in 10% neutral buffered formalin tube supplied by the study team. 
 
After being obtained, processing of the cores is as follows: all samples should be de-identified and 
labeled with the participant initials, participant study ID number and date of procedure. 
 
Individual participanting sites will obtain and store their on-treatment biopsy samples in local labs 
with the expectation that samples will later be shipped to the central study site (DFHCC) for 
analysis. Tumor specimens obtained at DFHCC will be delivered to: 
 
 
 
 
 
 
9.1.2 
Specimen Processing and Analysis 
 
Beyond targeted tumor genomic sequencing and PD-L1 tumor testing, tumor samples obtained on- 

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study will be stored for future gene and protein expression analyses, along with tumor immune 
profiling to be determined in the future. 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 28 days prior to study registration (except for 
pregnancy test and baseline tumor biopsy, as detailed below). If these screening assessments occur 3 
days before start of study treatment, then they may serve as the baseline Cycle 1 Day 1 values. Scans 
must be done within 28 days prior to study registration. 
 
As detailed in the Study Calendar, a negative pregnancy test in women of child-bearing potential 
must be documented within 72 hours before the first dose of study medication. 
 
Baseline laboratory evaluations must be completed within 14 days prior to study registration. In the 
event that the participant’s clinical condition is deteriorating, laboratory evaluations should be 
repeated within 48 hours of treatment initiation of the next cycle of therapy. 
 
Assessments must be performed prior to administration of any study agent. Study assessments and 
agents should be administered within  3 days of the protocol-specified date, unless otherwise noted. 

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Table of Events 
ScreeningA 
Lead-InB 
C1-3 
Day 1 
C4 Day 1 and 
beyond 
End of 
treatmentC 
Follow-upD 
EDC 
timepoints 
Duvelisib 
X 
X 
X 
Lead-in, day 1 
of each cycle 
Docetaxel 
X 
X 
Day 1 of each 
cycle 
Informed consent 
X 
N/A 
Demographics 
X 
Baseline 
Medical history 
X 
X 
X 
X 
X 
X 
Baseline 
Concurrent medicationsE 
X 
X 
X 
X 
X 
N/A 
Vital signs 
X 
X 
X 
X 
X 
N/A 
Physical exam 
X 
X 
X 
X 
X 
N/A 
Height 
X 
X 
X 
Baseline 
WeightF 
X 
X 
X 
X 
Baseline 
Performance statusG 
X 
X 
X 
X 
X 
X 
Baseline, EOT 
Hematology labs 
X 
X 
X 
X 
Baseline 
ChemistriesH 
X 
X 
X 
X 
Baseline 
Coagulation profileI 
X 
N/A 
Pregnancy testingJ 
X 
XJ 
Baseline 
Thyroid function testingK 
X 
Baseline, EOT 
Hepatitis testingL 
X 
Baseline 
CMV TestingM 
X 
Baseline 
ECG 
X 
Baseline 
Molecular and immune testingN 
Baseline 
Tumor biopsyO 
X 
XO 
Baseline, on- 
treatment 
Adverse event evaluation 
X 
X 
X 
X 
All visits 
Tumor measurementsP 
X 
X 
X 
Baseline, every 
3 cycles, EOT 
Patient reported surveysQ 
X 
X 
X 
X 
X 
Baseline, lead- 
in, every 3 
cycles, EOT 
A Baseline evaluations are to be conducted within 28 days prior to study registration (except for pregnancy test and baseline tumor biopsy) If these screening assessments occur 3 
days before start of study treatment, then they may serve as the baseline Cycle 1 Day 1 values  
B Participants will receive duvelisib 25 mg orally twice daily for 7 ± 2 days (1 week) prior to the initiation of the first cycle of docetaxel chemotherapy 
C All subjects will be asked to return to the site for a final, end-of-treatment visit (EOT), if possible This visit must be performed within 30 days of final administration of study 
treatment EOT assessments will not have to be repeated if the same assessments were performed within 7 days of this planned visit  
D Participants will be followed for best overall response and development and documentation of first disease progression and fo r survival throughout the course of the trial for 3 
years from the time of study registration Participants removed from protocol therapy for unacceptable adverse event and if they have not developed first disease progression at 
time of discontinuation of protocol therapy, will continue to be followed until first disease progression and survival until death or 3 years from study registration (whichever occurs 
first) 
E See Section 5 4 for details about concurrent medication administration (specifically CYP3A4 interactions), supportive care medication guidelines, and the use of recommended 
viral and infectious prophylaxis while on duvelisib Antimicrobial prophylaxis and pneumococcal pneumonia vaccine are recommended for subjects with history of or considered 
at high risk for infections and during periods of severe neutropenia Choice of antimicrobial agent (antifungal, antibiotic, antiviral) is per treating investigator discretion, but the 
restrictions on the use of CYP3A inducers, inhibitors, and substrates should be considered  
F Weight in kilograms (kg) should be used for docetaxel dosing per standard institutional practice 
G As per ECOG performance status scale (see Appendix A) 
H Routine chemistry labs include: a comprehensive metabolic panel with liver function tests; magnesium levels are discretionary per the investigator 
I Includes PT/INR and aPTT testing 
J Only required on day 1 of cycle 1 Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 7 days of study registr ation Female 
subjects of childbearing potential should have a negative urine or serum pregnancy test repeated within 72 hours prior to receiving the first dose of study medication If the urine 
test is positive or cannot be confirmed as negative, a serum pregnancy test will be required 
K TSH and free T4 if indicated with prior head and neck exposure 
L Hepatitis B virus and hepatitis C virus testing required Hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HbsAb), hepatitis B core antibody (HbcAb), and 
hepatitis C antibody (HCV antibody with reflex HCV PCR viral testing if HCV antibody positive) testing required  
M Subjects with a history of CMV infection/reactivation or viremia should be monitored for reactivation by polymerase chain reaction (PCR) or antigen test at least monthly 
Prophylactic treatment per institutional guidelines is recommended for subjects considered by investigators to be at high ris k for CMV reactivation 
N The results of tumor molecular (targeted nex-generation gene sequencing) and immune profiling (PD-L1 CPS) will be used to determine PD-L1 status, TP53 and PI3K pathway 
activation status These reports should be available at baseline prior to enrollment  
O A fresh tumor biopsy sample is not required prior to the start of duvelisib and docetaxel if an archival tissue sample is available for histologic confirmation of SCCHN An on- 
treatment tumor tissue biopsy will be offered at the end of cycle 2 (around week 6) but before cycle 3 (around week 9) in a subset of patients who are willing and able to undergo 
tissue sampling Details about collection and handling of the tumor biopsy specimen can be found in Section 9 
P Tumor assessment scans (contrast-enhanced CT or MRI of the neck; CT chest, abdomen, and pelvis or PET-CT) will be performed at screening/baseline After starting protocol, 
following the completion of 3 cycles of therapy, imaging will be repeated with a neck CT or MRI and chest CT (abdomen and pelvis CT are discretionary based on disease sites) or 
PET-CT at 9 week intervals (every 3 cycles) Post end of protocol treatment, if first local, locoregional, or distant recurrence has not been confirmed, imaging should co ntinue 
every 2-3 months (including a survival status update) until first disease progression is confirmed After documentation of first disease recurrence, only survival status will continue 
to be updated until death or 3 years post study registration (whichever occurs first) 
Q Quality of life surveys will be completed at screening, after completion of the lead-in phase, every 3 cycles, and at 30-day follow-up Patients will complete the EORTC QOL 
Module for Head and Neck Cancer (QLQ-C30 and HN35) 

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11. MEASUREMENT OF EFFECT 
 
11.1 
Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 9 weeks. In 
addition to a baseline scan, confirmatory scans should also be obtained 8 (not less than 4) weeks 
following initial documentation of objective response. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009]. Changes in the largest diameter (unidimensional measurement) of the 
tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
11.1.1 Definitions 
 
Evaluable for Target Disease response. Only those participants who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease re- 
evaluated will be considered evaluable for target disease response. These participants will 
have their response classified according to the definitions stated below. (Note: Participants 
who exhibit objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
Evaluable Non-Target Disease Response. Participants who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease. The response assessment is based on the presence, absence, 
or unequivocal progression of the lesions. 
 
11.1.2 Disease Parameters 
 
Measurable disease. Measurable lesions are defined as those that can be accurately measured 
in at least one dimension (longest diameter to be recorded) as ≥20 mm by chest x-ray or ≥10 
mm with CT scan, MRI, or calipers by clinical exam. All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
Note: Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable. If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the protocol. 
Malignant lymph nodes. To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis 
will be measured and followed. 
Non-measurable disease. All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are 

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considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
abdominal masses (not followed by CT or MRI), and cystic lesions are all considered non- 
measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above. However, if non-cystic 
lesions are present in the same participant, these are preferred for selection as target lesions. 
 
Target lesions. All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions 
in total, representative of all involved organs, should be identified as target lesions and 
recorded and measured at baseline. Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in 
addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible 
measurement in which circumstance the next largest lesion which can be measured 
reproducibly should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the baseline  
sum diameters. If lymph nodes are to be included in the sum, then only the short axis is 
added into the sum. The baseline sum diameters will be used as reference to further 
characterize any objective tumor regression in the measurable dimension of the disease. 
 
Non-target lesions. All other lesions (or sites of disease) including any measurable lesions 
over and above the 5 target lesions should be identified as non-target lesions and should also 
be recorded at baseline. Measurements of these lesions are not required, but the presence, 
absence, or in rare cases unequivocal progression of each should be noted throughout follow 
up. 
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a 
digital measurement tool. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
To the greatest extent possible the same method of assessment and the same techniques 
should be used to characterize each identified and reported lesion at baseline and during each 
follow-up, however exceptions may be made for the development of contrast alleriges and/or 
other extenuating circumstances, at the discretion of the treating investigator. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 

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Clinical lesions. Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in diameter as  
assessed using calipers (e.g., skin nodules). In the case of skin lesions, documentation by 
color photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Conventional CT and MRI. This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT thickness is 5mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size of a measurable lesion should be twice the slice 
thickness. MRI is also acceptable in certain situations (e.g. for body scans). 
 
Use of MRI remains a complex issue. MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement. Furthermore, the 
availability of MRI is variable globally. As with CT, if an MRI is performed, the technical 
specifications of the scanning sequences used should be optimized for the evaluation of the 
type and site of disease. Furthermore, as with CT, the modality used at follow-up should be 
the same as was used at baseline and the lesions should be measured/assessed on the same 
pulse sequence. It is beyond the scope of the RECIST guidelines to prescribe specific MRI 
pulse sequence parameters for all scanners, body parts, and diseases. Ideally, the same type 
of scanner should be used and the image acquisition protocol should be followed as closely 
as possible to prior scans. Body scans should be performed with breath-hold scanning 
techniques, if possible. 
 
PET-CT. At present, the low dose or attenuation correction CT portion of a combined PET- 
CT is not always of optimal diagnostic CT quality for use with RECIST measurements. 
However, if the site can document that the CT performed as part of a PET-CT is of identical 
diagnostic quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the 
PET-CT can be used for RECIST measurements and can be used interchangeably with 
conventional CT in accurately measuring cancer lesions over time. Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator if it is not 
routinely or serially performed. 
 
Cytology, Histology. These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease. 
 
11.1.4 Response Criteria 
 
11.1.4.1 
Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph 
nodes (whether target or non-target) must have reduction in short axis to <10 mm. 

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Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or 
more new lesions is also considered progressions). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase 
to qualify for PD, taking as reference the smallest sum diameters while on study. 
 
11.1.4.2 
Evaluation of Non-Target Lesions 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (<10 mm short 
axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Progressive Disease (PD): Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. Unequivocal progression should not normally 
trump target lesion status. It must be representative of overall disease status change, not a 
single lesion increase. 
Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or overall study PI). 
11.1.4.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in scanning 
technique, imaging modality, or findings thought to represent something other than tumor 
(for example, some ‘new’ bone lesions may be simply healing or flare of pre-existing 
lesions). However, a lesion identified on a follow-up scan in an anatomical location that 
was not scanned at baseline is considered new and will indicate PD. If a new lesion is 
equivocal (because of small size etc.), follow-up evaluation will clarify if it truly 
represents new disease and if PD is confirmed, progression should be declared using the 
date of the initial scan on which the lesion was discovered. 
 
11.1.4.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started). The patient's best response 

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assignment will depend on the achievement of both measurement and confirmation 
criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not 
evaluated 
No 
SD 
Documented at least once >4 wks from 
baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions may be 
accepted as disease progression. 
Note: Participants with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.” Every effort should 
be made to document the objective progression even after discontinuation of treatment. 
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an 
endpoint for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not 
advised 
 
11.1.5 Duration of Response 
 
Duration of overall response: The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date 
that recurrent or progressive disease is objectively documented (taking as reference for 
progressive disease the smallest measurements recorded since the treatment started, or death 
due to any cause. Participants without events reported are censored at the last disease 
evaluation). 
 
Duration of overall complete response: The duration of overall CR is measured from the time 
measurement criteria are first met for CR until the first date that progressive disease is 
objectively documented, or death due to any cause. Participants without events reported are 
censored at the last disease evaluation. 

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Duration of stable disease: Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements. 
 
11.1.6 Survival and Clinical Parameters 
 
Overall Survival: Overall Survival (OS) is defined as the time from registration to death due 
to any cause, or censored at date last known alive. 
Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time from 
registration to the earlier of progression or death due to any cause. Participants alive without 
disease progression are censored at date of last disease evaluation. 
Time to Progression: Time to Progression (TTP) is defined as the time from registration to 
progression, or censored at date of last disease evaluation for those without progression 
reported. 
Clinical benefit rate: defined as CR, PR and stable disease (SD) ≥24 weeks. 
 
11.1.7 Response Review 
 
For trials where the response rate is the primary endpoint, it is strongly recommended that all 
responses be reviewed by an expert(s) independent of the study at the study’s completion. 
Simultaneous review of the participants’ files and radiological images is the best approach. 
 
11.1.8 Quality of life measurements 
 
Quality of Life Assessment: The EORTC QOL Module for Head and Neck Cancer (QLQ- 
C30 and HN35) will be used to assess the effect of cancer treatment on physical, social and 
emotional well-being and function. The survey consists of 30 and 35 items, respectively. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on the 
data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites are responsible for submitting data and/or data forms to the Office of Data Quality 
(ODQ) in accordance with DF/HCC policies. 

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12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity and 
accrual data from this study. The committee is composed of medical oncologists, research nurses, 
pharmacists and biostatisticians with direct experience in cancer clinical research. Information that 
raises any questions about participant safety will be addressed with the Sponsor-Investigator and 
study team. 
The DSMC generally reviews each protocol up to four times a year with the frequency determined 
by the outcome of previous reviews. Information to be provided to the committee may include: up- 
to-date participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported across all sites; summary of all deaths occurring 
within 30 days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all 
deaths while being treated and during active follow-up; any response information; audit results, and 
a summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request. 
12.3 
Multi-Center Guidelines 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan. The specific responsibilities of the overall study PI, Coordinating Center, 
and Participating Institutions and the procedures for auditing are presented in Appendix B. 
 
The Overall PI/Coordinating Center is responsible for distributing all IND Action Letters or Safety 
Reports to all participating institutions for submission to their individual IRBs for action as required. 
Secura Bio will be copied on all such reports in a timely fashion. 
• 
•  
Mechanisms will be in place to ensure quality assurance, protocol compliance, and 
adverse event reporting at each site. 
•  
Except in very unusual circumstances, each participating institution will order the 
study agent(s) directly from supplier. A participating site may order the agent(s) only after 
the initial IRB approval for the site has been forwarded to the Coordinating Center. 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
A Simon optimal two-stage design will be utilized. The primary hypothesis is that the combination 
of duvelisib and docetaxel will increase the overall response rate (ORR) in this PD-1 inhibitor 
refractory patient population. Under the standard-of-care, we expect an ORR less than 10% [Table 1 
above] for this population. We anticipate that an ORR of 30% would represent a clinically important 
advance. 
Thirteen evaluable patients (eligible and begin protocol treatment) are to be entered into the first 
stage including those in lead-in stage. If there are ≤ 1 patients with disease in response, accrual to 
this trial will be closed with the expectation that there is little evidence that the response rate will 

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reach 30%. The probability that the trial will close early is 62% if the true response rate is 10%. If 
there are >1 evaluable patients with disease in response, accrual will continue until a total of 26 
evaluable patients are registered to the trial. If there are >4 evaluable patients with disease in 
response among 26 evaluable patients, further testing of this regimen will be considered. If the true 
response rate is 30%, the probability of concluding the regimen is effective is 89.2%, if the true 
response rate is 10%, the probability of concluding the regimen is effective is 9.8%. 
 
13.2 
Sample Size and Accrual Rate 
 
To account for patients who are registered to the trial but do not begin protocol treatment an 
additional 4 patients could be enrolled, for a total of up to N=30 patients registered. 
With three planned sites throughout the U.S. at academic centers in major cities, we anticipate 
accruing 1-2 patients per month for a total enrollment period of 12 months for 26 planned subjects. 
Due to possible delays in initiation of approval at other sites and/or initiation of accrual itself, the 
accrual period could take longer. As is customary with two-stage designs, accrual will be suspended 
after the first stage in order to assess outcome; however, this suspension is also dependent on the 
actual observed accrual rate and the number of patients with confirmation of disease response status 
while the first stage of the trial is accruing. 
13.3 
Stratification Factors 
 
There are no stratification factors in this trial. 
 
13.4 
Interim Monitoring Plan 
 
Interim analysis will be conducted after the first stage which has 13 evaluable patients enrolled (refer 
to Section 13.1). 
 
Safety run-in: An initial safety run-in cohort of 3 patients is planned prior to enrolling the remainder 
of the study cohort with a safety pause to ensure tolerability of the regimen. 
 
The following stopping rule will be used to monitor excessive protocol treatment related 
toxicity/delays (as noted in Sectio 6.4): if 3 or more of the first 10 patients (which includes the 3 
patients treated as part of the safety run-in) who begin protocol treatment experience treatment 
related toxicities, accrual to the trial will be suspended to further evaluate the events and decisions 
made regarding the overall status of the trial. If the true rate due to toxicity is 10% then the 
probability of suspending accrual is 7%; if the true rate is 20%, then the probability of suspending 
accrual is 32.2%; if the true rate due to toxicity is 30% then the probability of suspending accrual is 
62%. 
 
13.5 
Analysis of Primary Endpoint 
 
The primary efficacy population includes all eligible patients who begin protocol treatment. Best 
overall response will be summarized as a proportion with a corresponding exact 95% confidence 
interval (CI) (if the trial closes to accrual after the first stage), or a corresponding 95% two-stage CI 
if the trial closes to accrual after the second stage. 

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13.6 
Analysis of Secondary Endpoints 
 
For the secondary endpoints, the Kaplan-Meier method will be used to estimate time-to-event 
endpoints with corresponding 95% confidence intervals for the median or time-specific event time. 
Another endpoint is to assess patient-reported quality of life (QOL). QOL will be assessed via self- 
report questionnaires at the timepoints outlined in the Study Calendar (Section 10). Descriptive 
statistics from the questionnaires will be summarized across timepoints of assessment. Rates of drop- 
out/non-response to QOL assessments and corresponding reason will also be summarized across 
timepoints of assessment. 
Molecular and immune correlative studies are also planned for the future. Given the small sample 
size of this trial, these studies are exploratory. Information on markers from samples will be 
summarized descriptively. Within subject changes (paired) in these molecular markers will be 
analyzed. 
14. PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of the 
study is the time point at which the last data items are to be reported, or after the outcome data are 
sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate and Study 
Duration (Section 13.0). If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three (3) 
years after the end of the study. The overall study PI (Glenn J. Hanna, M.D.) will be responsible for 
reporting and publishing the data. Secura Bio shall be given the opportunity to comment on all 
potential publications related to the Study, and good faith efforts shall be made to incorporate such 
comments, as scientifically appropriate, prior to submission for publication. 
 
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16. APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 

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1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out 
any work activities. Up and about more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to 
bed or chair. 
5 
Dead. 

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