Phase Ib/II Study of MEDI4736 Evaluated in Different Combinations in Metastatic Pancreatic Ductal Carcinoma

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02583477
• Collaborator: (none)
• Enrollment: 23
• Locations: 7
• Arms: 2
• Actual Duration (Months): 27.5
• Patients Per Site: 3.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 Evaluated in Different Combinations (with chemotherapy or AZD5069) in Patients with Metastatic Pancreatic Ductal Adenocarcinoma

Condition or Disease	Intervention/Treatment	Phase
Metastatic Pancreatic Ductal Adenocarcinoma	Drug: MEDI4736 in combination with nab-paclitaxel and gemcitabine; Drug: MEDI4736 in combination with AZD5069	Phase 1/Phase 2

Detailed Description

This is a Phase Ib and II open-label, multi-center study to evaluate the safety, tolerability, pharmacodynamics, and antitumor activity of MEDI4736 in combination with chemotherapy or AZD5069 in patients with pancreatic ductal adenocarcinoma (PDAC). This study will consist of 2 independent cohorts.

Study Design

• Study Type: Interventional
• Actual Enrollment: 23 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase Ib and II Open-Label, Multi-Center Study of MEDI4736 Evaluated in Different Combinations in Patients With Metastatic Pancreatic Ductal Adenocarcinoma
• Actual Study Start Date: Mar 25, 2016
• Actual Primary Completion Date: Jul 9, 2018
• Actual Study Completion Date: Jul 9, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: MEDI4736 +nab-paclitaxel + gemcitabine MEDI4736 in combination with nab-paclitaxel + gemcitabine chemotherapy regimen via IV infusion	Drug: MEDI4736 in combination with nab-paclitaxel and gemcitabine; MEDI4736 in combination with nab-paclitaxel + gemcitabine chemotherapy regimen via IV infusion
Experimental: MEDI4736+AZD5069 MEDI4736 via IV infusion and oral AZD5069	Drug: MEDI4736 in combination with AZD5069; MEDI4736 via IV infusion and oral AZD5069

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose-Limiting Toxicities (DLT) [Cohort 1: From time of first dose of MEDI4736 on Day 1 up to Day 28 of Cycle 1 and Cohort 2: From time of first dose of AZD5069 and MEDI4736 on Day 1 up to Day 28 of Cycle 1 or until a participant experiences a DLT, whichever occurs first.]

   DLT period was defined as first treatment cycle for Cohort 1, and first dose of AZD5069 and MEDI4736 to end of Cycle 1 or until a participant experienced a DLT, whichever occurs first for Cohort 2. A DLT was defined as any of below listed laboratory abnormalities or adverse events (AE) related to MEDI4736 collected during DLT period. Liver transaminase elevation >= 5× but <= 8× upper limit of normal (ULN) that doesn't resolve to Grade 2 within 5 days Transaminase elevation > 8× ULN or total bilirubin > 5× ULN Any Grade 4 immune-related AE (irAE) not attributed to local tumor response, Grade >=3 colitis, Grade >=2 pneumonitis that doesn't resolve to <= Grade 1 within 7 days, Grade 3 irAE, that doesn't resolve to Grade <=1 or baseline status within 14 days Any Grade >=3 non-irAE toxicity that doesn't resolve to Grade <=1 or baseline status within 14 days A DLT was defined as any Grade 3 or worse AE related to AZD5069 that occurs from first dose of AZD5069 up to end of DLT period.

2. Number of Participants With AEs [From first dose of study treatment administration (Day 1) until 90 days after the last dose of IP or initiation of the first subsequent anticancer therapy (whichever occurred first), approximately 30 months.]

   An AE is the development of an undesirable medical condition or deterioration of a pre-existing medical condition following or during exposure to study treatment, whether or not considered causally related to study treatment. An undesirable medical condition can be symptoms, signs or abnormal results of an investigation. A serious AE (SAE) is an AE that fulfills one or more following criteria: death, life-threatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity or substantial disruption of ability to conduct normal life functions, congenital abnormality or birth defect, and an important medical event that may jeopardize participant or may require medical intervention to prevent one of outcomes listed above. AEs leading to discontinuation of study treatment were those with action taken was 'Drug Permanently Discontinued' for any study treatment. Only treatment emergent AEs were presented.

3. Objective Response Rate (ORR) in Cohort 2 [RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.]

   ORR is defined as the percentage of participants with a confirmed overall response of complete response (CR) or partial response (PR). A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit and confirmed by repeat imaging, preferably at the next regularly scheduled imaging visit and not less than 4 weeks after the visit when the response was first observed with no evidence of progression between the initial and CR/PR confirmation visit. CR is defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of TLs, taking as reference the baseline sum of diameters as long as criteria for PD were not met. ORR was determined using Investigator assessments according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).

Secondary Outcome Measures

1. Duration of Response (DoR) in Cohort 2 [RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.]

   DoR was defined as the time from the first documentation of CR/PR (which is subsequently confirmed) until the date of progression/death, or the last evaluable RECIST assessment for participants that did not progress or did progress after 2 missed visits of the last evaluable assessment (or first dose). PD was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. DoR was determined using Investigator assessments according to RECIST v1.1 and was calculated using the Kaplan-Meier technique.

2. Disease Control Rate (DCR) in Cohort 2 [RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days for first 48 weeks up to 6 months and 12 months]

   DCR at 6 months is defined as the percentage of participants who had a best objective response (BoR) of CR or PR in the first 6 months (i.e. 24+1=25 weeks to allow for a late assessment within the assessment window) or who had demonstrated stable disease (SD) for a minimum interval of 24 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 161 days) following the start of treatment. DCR at 12 months is defined as the percentage of participants who had a BoR of CR or PR in the first 12 months (i.e. 48+1=49 weeks to allow for a late assessment within the assessment window) or who had demonstrated SD for a minimum interval of 48 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 329 days) following the start of treatment. DCR was determined using Investigator assessments according to RECIST v1.1.

3. Median Progression-Free Survival (PFS) in Cohort 2 [RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.]

   PFS is defined as the time from the date of first dose until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraws from allocated therapy or receives another anticancer therapy prior to progression. PFS was determined using Investigator assessments according to RECIST v1.1 and calculated using the Kaplan-Meier technique.

4. Progression-Free Survival Rate at 3 Months (PFS3) in Cohort 2 [RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days up to 3 months]

   The PFS rate was defined as percentage of participants alive and progression-free after 3 months. The PFS3 was calculated using Kaplan-Meier estimates. Tumor progression was determined based on Investigator assessment and RECIST v1.1.

5. Progression-Free Survival Rate at 6 Months (PFS6) in Cohort 2 [RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days up to 6 months]

   The PFS6 was defined as percentage of participants alive and progression-free after 6 months. The PFS6 was calculated using Kaplan-Meier estimates. Tumor progression was determined based on Investigator assessment and RECIST v1.1.

6. Median Overall Survival (OS) in Cohort 2 [RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.]

   OS is defined as the time from the date of first dose until death due to any cause (i.e. date of death or censoring - date of first dose + 1). OS was calculated using the Kaplan-Meier technique. Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive (censored at end of study).

7. Overall Survival at 6 Months (OS6) in Cohort 2 [From first dose of study treatment (Day 1) up to 6 months]

   OS6 is defined as percentage of participants alive at 6 months from first dose of study treatment. OS6 was calculated using the Kaplan-Meier estimate of OS at 6 months.

8. Overall Survival at 12 Months (OS12) in Cohort 2 [From first dose of study treatment (Day 1) up to 12 months]

   OS12 is defined as percentage of participants alive at 12 months from first dose of study treatment. OS12 was calculated using the Kaplan-Meier estimate of OS at 12 months.

9. Number of Participants With Anti-Drug Antibody (ADAs) for MEDI4736 in Cohort 2 [On Day 1 of Cycles 1, 2, 3, 4, and 7; At months 3 and 6 after last dose]

   Samples were measured for the presence of ADAs and ADA-neutralizing antibodies for MEDI4736 using validated assays. Persistently positive is defined as positive at >=2 post-baseline assessments or positive at the last post-baseline assessment. Transiently positive is defined as having at least one post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive. NAB = neutralizing antibody.

10. Mean Plasma Concentrations of MEDI4736 in Cohort 2 [Predose (within 60 minutes prior to treatment with any IP) on Day 1 of Cycles 1, 2, 3, 4, and 7; and post infusion (within 10 minutes after end of MEDI4736 infusion) on Day 1 of Cycles 1 and 7]

    Mean peak and trough plasma concentrations of MEDI4736 are presented.

11. Mean Plasma Concentrations of AZD5069 in Cohort 2 [Predose (within 60 minutes prior to treatment with any IP) on Day 1 of Cycles 1, 2, 3, 4, and 7; and postdose (within 10 minutes after end of MEDI4736 infusion) on Day 1 of Cycles 1, 2, and 7]

    Mean peak and trough plasma concentration of AZD5069 are presented. Concentration of AZD5069 was calculated by plasma concentration-time profile.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Histologically or cytologically confirmed metastatic PDAC, no more than 1 prior chemotherapy regimen or treatment-naïve patients

2. Eastern Cooperative Oncology Group 0 or 1

3. At least 1 lesion, not previously irradiated, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes, which must have short axis ≥15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) scan and that is suitable for accurate repeated measurements

4. MEDI4736 + nab-paclitaxel + gemcitabine chemotherapy cohort: treatment-naïve patients with metastatic PDAC who have received no previous systemic chemotherapy 5 MEDI4736 + Cohort: Patient should receive no more than 1 prior systemic chemotherapy regimen.

5. Life expectancy ≥ 12 weeks. 7. ECOG PS of 0 or 1 8. Adequate organ and bone marrow function 9. Ability to undergo during screening a tumor biopsy that is adequate for biomarker analysis.

Exclusion Criteria:

1. Any concurrent chemotherapy, investigational product , biologic, or hormonal therapy for cancer treatment.

2. Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, whichever is shorter, prior to the first dose of study treatment.

3. Major surgical procedure within 21 days prior to the first dose of IP.

4. Patients weighing less than 30 kg

5. History of leptomeningeal carcinomatosis

6. Ascites requiring intervention

7. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy

8. Current or prior use of immunosuppressive medication within 14 days of first dose

9. Brain metastases or spinal cord compression.

10. Medi4736+AZD5069 Cohort only: received any potent and moderate cytochrome CYP3A4 inhibitors, potent and moderate CYP3A4 inducers, P-gp substrates, BCRP substrates, sensitive CYP2B6 substrates, warfarin and coumarin derivatives, or herbal supplements within 14 days of the first dose of study treatment

11. Uncontrolled intercurrent illness

12. Other malignancy within 5 years except for noninvasive malignancies

13. Mean QT interval ≥470 ms

14. Active infection

15. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP

16. Female patients who are pregnant or breastfeeding, or male or female patients of reproductive potential who are not employing an effective method of birth control

17. Prior exposure to immune-mediated therapy

18. Known allergy or hypersensitivity to IP formulations or to other human monoclonal antibodies

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Rochester	New York	United States	14642
2	Research Site	Cambridge		United Kingdom	CB2 0QQ
3	Research Site	Glasgow		United Kingdom	G12 0YN
4	Research Site	London		United Kingdom	SE1 9RY
5	Research Site	London		United Kingdom	W12 0NN
6	Research Site	Manchester		United Kingdom	M20 4BX
7	Research Site	Wirral		United Kingdom	CH63 4JY

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Jeff Evans, M.D, Beatson Institute, University of Glasgow, Garscrube Estate, Switchback Rd. Glasgow, UK, G61 1BD

Study Documents (Full-Text)

• Study Protocol - Feb 8, 2018
• Statistical Analysis Plan - Aug 2, 2018

More Information

Additional Information:

• CSP redacted
• SAP redacted

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT02583477
• Other Study ID Numbers: D4198C00003
• First Posted: Oct 22, 2015
• Last Update Posted: Aug 14, 2019
• Last Verified: Jul 1, 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by AstraZeneca: Pancreatic Ductal Adenocarcinoma, PDAC, immunotherapy, PDL1, AZD5069, MEDI4736
• Additional relevant MeSH terms: Adenocarcinoma; Gemcitabine; Paclitaxel; Durvalumab; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	This study consisted of 2 independent cohorts, each of which ran at separate times between 25 March 2016 and 09 July 2018. In Cohort 1, participants were recruited from 1 center in the United States; in Cohort 2, participants were recruited from 6 centers in the United Kingdom.
Pre-assignment Detail	Participants underwent screening evaluations to determine eligibility within 4 weeks (28 days) prior to first administration of the Investigational Product (IP). A total of 27 participants (3 in Cohort 1 and 24 in Cohort 2) were assigned to treatment and 23 were treated. Only treated participants are included in the participant flow.

Arm/Group Title	Cohort 1 (MEDI4736 + Nab-paclitaxel + Gemcitabine)	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic pancreatic ductal adenocarcinoma (PDAC) who were treatment naive received MEDI4736 1.5 gram (g) intravenous (IV) infusion on Day 1 of each 28-day cycle (q4w). Participants also received nab-paclitaxel 125 milligram per meter square (mg/m^2) IV infusion followed by gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Treatment continued until either confirmed progressive disease (PD) unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally twice daily (bid). The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Period Title: Overall Study
STARTED	3	20
Received Treatment	3	20
Completed Treatment	0	0
COMPLETED	0	0
NOT COMPLETED	3	20

Baseline Characteristics

Arm/Group Title	Cohort 1 (MEDI4736 + Nab-paclitaxel + Gemcitabine)	Cohort 2 (MEDI4736 + AZD5069)	Total
Arm/Group Description	Participants with metastatic PDAC who were treatment naive received MEDI4736 1.5 g IV infusion q4w. Participants also received nab-paclitaxel 125 mg/m^2 IV infusion followed by gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Treatment continued until either confirmed PD unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.	Total of all reporting groups
Overall Participants	3	20	23
Age, Customized (Count of Participants)
<50 years	0 0%	4 20%	4 17.4%
>=50 - <65 years	1 33.3%	12 60%	13 56.5%
>=65 - <75 years	2 66.7%	4 20%	6 26.1%
Sex: Female, Male (Count of Participants)
Female	2 66.7%	9 45%	11 47.8%
Male	1 33.3%	11 55%	12 52.2%
Race/Ethnicity, Customized (Count of Participants)
Asian	0 0%	1 5%	1 4.3%
White	3 100%	18 90%	21 91.3%
Other	0 0%	1 5%	1 4.3%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose-Limiting Toxicities (DLT)
Description	DLT period was defined as first treatment cycle for Cohort 1, and first dose of AZD5069 and MEDI4736 to end of Cycle 1 or until a participant experienced a DLT, whichever occurs first for Cohort 2. A DLT was defined as any of below listed laboratory abnormalities or adverse events (AE) related to MEDI4736 collected during DLT period. Liver transaminase elevation >= 5× but <= 8× upper limit of normal (ULN) that doesn't resolve to Grade 2 within 5 days Transaminase elevation > 8× ULN or total bilirubin > 5× ULN Any Grade 4 immune-related AE (irAE) not attributed to local tumor response, Grade >=3 colitis, Grade >=2 pneumonitis that doesn't resolve to <= Grade 1 within 7 days, Grade 3 irAE, that doesn't resolve to Grade <=1 or baseline status within 14 days Any Grade >=3 non-irAE toxicity that doesn't resolve to Grade <=1 or baseline status within 14 days A DLT was defined as any Grade 3 or worse AE related to AZD5069 that occurs from first dose of AZD5069 up to end of DLT period.
Time Frame	Cohort 1: From time of first dose of MEDI4736 on Day 1 up to Day 28 of Cycle 1 and Cohort 2: From time of first dose of AZD5069 and MEDI4736 on Day 1 up to Day 28 of Cycle 1 or until a participant experiences a DLT, whichever occurs first.

Outcome Measure Data

Analysis Population Description

For Cohort 1: Participants who completed DLT evaluation period and/or discontinued study treatment early due to a DLT and who have not missed >=2 infusions of gemcitabine. For Cohort 2: Participants who received 50% of planned doses of AZD5069 during DLT period as well as MEDI4736 infusion and remained active on study at end of Day 28 of Cycle 1.

Arm/Group Title	Cohort 1 (MEDI4736 + Nab-paclitaxel + Gemcitabine)	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC who were treatment naive received MEDI4736 1.5 g IV infusion q4w. Participants also received nab-paclitaxel 125 mg/m^2 IV infusion followed by gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Treatment continued until either confirmed PD unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	3	12
Count of Participants [Participants]	0 0%	4 20%

2. Primary Outcome

Title	Number of Participants With AEs
Description	An AE is the development of an undesirable medical condition or deterioration of a pre-existing medical condition following or during exposure to study treatment, whether or not considered causally related to study treatment. An undesirable medical condition can be symptoms, signs or abnormal results of an investigation. A serious AE (SAE) is an AE that fulfills one or more following criteria: death, life-threatening, in-patient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity or substantial disruption of ability to conduct normal life functions, congenital abnormality or birth defect, and an important medical event that may jeopardize participant or may require medical intervention to prevent one of outcomes listed above. AEs leading to discontinuation of study treatment were those with action taken was 'Drug Permanently Discontinued' for any study treatment. Only treatment emergent AEs were presented.
Time Frame	From first dose of study treatment administration (Day 1) until 90 days after the last dose of IP or initiation of the first subsequent anticancer therapy (whichever occurred first), approximately 30 months.

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who received at least 1 dose of IP and for whom any post-dose data were available.

Arm/Group Title	Cohort 1 (MEDI4736 + Nab-paclitaxel + Gemcitabine)	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC who were treatment naive received MEDI4736 1.5 g IV infusion q4w. Participants also received nab-paclitaxel 125 mg/m^2 IV infusion followed by gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Treatment continued until either confirmed PD unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	3	20
Any AE	3 100%	20 100%
Any AE causally related to treatment (CRT)	3 100%	14 70%
Any AE of CTCAE Grade 3 or higher	3 100%	18 90%
Any AE of CTCAE Grade 3 or higher CRT	3 100%	10 50%
Any AE leading discontinuation of study treatment	2 66.7%	3 15%
Any AE with outcome of death	1 33.3%	4 20%
Any AE with outcome of death CRT	1 33.3%	0 0%
Any SAE	1 33.3%	16 80%
Any SAE CRT	1 33.3%	8 40%

3. Primary Outcome

Title	Objective Response Rate (ORR) in Cohort 2
Description	ORR is defined as the percentage of participants with a confirmed overall response of complete response (CR) or partial response (PR). A confirmed response of CR/PR means that a response of CR/PR is recorded at 1 visit and confirmed by repeat imaging, preferably at the next regularly scheduled imaging visit and not less than 4 weeks after the visit when the response was first observed with no evidence of progression between the initial and CR/PR confirmation visit. CR is defined as disappearance of all target lesions (TLs) since baseline. Any pathological lymph nodes selected as TLs must have a reduction in short axis to <10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters of TLs, taking as reference the baseline sum of diameters as long as criteria for PD were not met. ORR was determined using Investigator assessments according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1).
Time Frame	RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.

Outcome Measure Data

Analysis Population Description

The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.

Arm/Group Title	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	18
Number (80% Confidence Interval) [percentage of participants]	5.6 186.7%

4. Secondary Outcome

Title	Duration of Response (DoR) in Cohort 2
Description	DoR was defined as the time from the first documentation of CR/PR (which is subsequently confirmed) until the date of progression/death, or the last evaluable RECIST assessment for participants that did not progress or did progress after 2 missed visits of the last evaluable assessment (or first dose). PD was defined as at least a 20% increase in the sum of diameters of TLs, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. DoR was determined using Investigator assessments according to RECIST v1.1 and was calculated using the Kaplan-Meier technique.
Time Frame	RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.

Outcome Measure Data

Analysis Population Description

The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation. Participants with confirmed response were evaluated, only one participant showed response.

Arm/Group Title	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	1
Median (Inter-Quartile Range) [weeks]	18.29

5. Secondary Outcome

Title	Disease Control Rate (DCR) in Cohort 2
Description	DCR at 6 months is defined as the percentage of participants who had a best objective response (BoR) of CR or PR in the first 6 months (i.e. 24+1=25 weeks to allow for a late assessment within the assessment window) or who had demonstrated stable disease (SD) for a minimum interval of 24 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 161 days) following the start of treatment. DCR at 12 months is defined as the percentage of participants who had a BoR of CR or PR in the first 12 months (i.e. 48+1=49 weeks to allow for a late assessment within the assessment window) or who had demonstrated SD for a minimum interval of 48 weeks (minus 1 week to allow for an early assessment within the assessment window, i.e. 329 days) following the start of treatment. DCR was determined using Investigator assessments according to RECIST v1.1.
Time Frame	RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days for first 48 weeks up to 6 months and 12 months

Outcome Measure Data

Analysis Population Description

The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.

Arm/Group Title	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	18
At 6 months	11.1 370%
At 12 months	5.6 186.7%

6. Secondary Outcome

Title	Median Progression-Free Survival (PFS) in Cohort 2
Description	PFS is defined as the time from the date of first dose until the date of objective disease progression or death (by any cause in the absence of progression) regardless of whether the participant withdraws from allocated therapy or receives another anticancer therapy prior to progression. PFS was determined using Investigator assessments according to RECIST v1.1 and calculated using the Kaplan-Meier technique.
Time Frame	RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.

Outcome Measure Data

Analysis Population Description

The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.

Arm/Group Title	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	18
Median (95% Confidence Interval) [months]	1.6

7. Secondary Outcome

Title	Progression-Free Survival Rate at 3 Months (PFS3) in Cohort 2
Description	The PFS rate was defined as percentage of participants alive and progression-free after 3 months. The PFS3 was calculated using Kaplan-Meier estimates. Tumor progression was determined based on Investigator assessment and RECIST v1.1.
Time Frame	RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days up to 3 months

Outcome Measure Data

Analysis Population Description

The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.

Arm/Group Title	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	18
Number (80% Confidence Interval) [percentage of participants]	11.1 370%

8. Secondary Outcome

Title	Progression-Free Survival Rate at 6 Months (PFS6) in Cohort 2
Description	The PFS6 was defined as percentage of participants alive and progression-free after 6 months. The PFS6 was calculated using Kaplan-Meier estimates. Tumor progression was determined based on Investigator assessment and RECIST v1.1.
Time Frame	RECIST assessments were performed at baseline (within 28 days before start of study treatment) and every 6 weeks +/- 7 days up to 6 months

Outcome Measure Data

Analysis Population Description

The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.

Arm/Group Title	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	18
Number (80% Confidence Interval) [percentage of participants]	11.1 370%

9. Secondary Outcome

Title	Median Overall Survival (OS) in Cohort 2
Description	OS is defined as the time from the date of first dose until death due to any cause (i.e. date of death or censoring - date of first dose + 1). OS was calculated using the Kaplan-Meier technique. Any participant not known to have died at the time of analysis was censored based on the last recorded date on which the participant was known to be alive (censored at end of study).
Time Frame	RECIST assessments performed at baseline (within 28 days before start of study treatment), every 6 weeks +/-7 days for first 48 weeks, then every 12 weeks +/-7 days thereafter until confirmed objective disease progression. Up to approximately 30 months.

Outcome Measure Data

Analysis Population Description

The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.

Arm/Group Title	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	18
Median (95% Confidence Interval) [months]	2.8

10. Secondary Outcome

Title	Overall Survival at 6 Months (OS6) in Cohort 2
Description	OS6 is defined as percentage of participants alive at 6 months from first dose of study treatment. OS6 was calculated using the Kaplan-Meier estimate of OS at 6 months.
Time Frame	From first dose of study treatment (Day 1) up to 6 months

Outcome Measure Data

Analysis Population Description

The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.

Arm/Group Title	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	18
Number (80% Confidence Interval) [percentage of participants]	22.2 740%

11. Secondary Outcome

Title	Overall Survival at 12 Months (OS12) in Cohort 2
Description	OS12 is defined as percentage of participants alive at 12 months from first dose of study treatment. OS12 was calculated using the Kaplan-Meier estimate of OS at 12 months.
Time Frame	From first dose of study treatment (Day 1) up to 12 months

Outcome Measure Data

Analysis Population Description

The efficacy analysis set included all participants who received at least 1 dose of IP and with no important protocol deviation that could impact the efficacy evaluation.

Arm/Group Title	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	18
Number (80% Confidence Interval) [percentage of participants]	14.8 493.3%

12. Secondary Outcome

Title	Number of Participants With Anti-Drug Antibody (ADAs) for MEDI4736 in Cohort 2
Description	Samples were measured for the presence of ADAs and ADA-neutralizing antibodies for MEDI4736 using validated assays. Persistently positive is defined as positive at >=2 post-baseline assessments or positive at the last post-baseline assessment. Transiently positive is defined as having at least one post-baseline ADA positive assessment and not fulfilling the conditions of persistently positive. NAB = neutralizing antibody.
Time Frame	On Day 1 of Cycles 1, 2, 3, 4, and 7; At months 3 and 6 after last dose

Outcome Measure Data

Analysis Population Description

The safety analysis set included all participants who received at least 1 dose of IP and for whom any post-dose data were available.

Arm/Group Title	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	20
Positive at any visit	3 100%
Both baseline and post-baseline positive	0 0%
Only post-baseline positive	1 33.3%
Only baseline positive	2 66.7%
ADA persistently positive	0 0%
ADA transiently positive	1 33.3%
ADA positive participants who are NAB positive	0 0%

13. Secondary Outcome

Title	Mean Plasma Concentrations of MEDI4736 in Cohort 2
Description	Mean peak and trough plasma concentrations of MEDI4736 are presented.
Time Frame	Predose (within 60 minutes prior to treatment with any IP) on Day 1 of Cycles 1, 2, 3, 4, and 7; and post infusion (within 10 minutes after end of MEDI4736 infusion) on Day 1 of Cycles 1 and 7

Outcome Measure Data

Analysis Population Description

The Pharmacokinetic (PK) analysis set included all participants who received at least 1 dose of IP per protocol for whom any post-dose data were available and who did not violate or deviate from the protocol in ways that would significantly affect the PK analyses.

Arm/Group Title	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	20
Cycle 1 Day 1: Predose	1444.730 (1010.7667)
Cycle 1 Day 1: Post infusion	339342.229 (95923.6405)
Cycle 2 Day 1: Predose	56773.555 (17716.8788)
Cycle 3 Day 1: Predose	63655.840 (26425.8402)
Cycle 4 Day 1: Predose	69325.233 (22750.3387)
Cycle 7 Day 1: Predose	79687.820 (NA)
Cycle 7 Day 1: Post infusion	435297.610 (NA)

14. Secondary Outcome

Title	Mean Plasma Concentrations of AZD5069 in Cohort 2
Description	Mean peak and trough plasma concentration of AZD5069 are presented. Concentration of AZD5069 was calculated by plasma concentration-time profile.
Time Frame	Predose (within 60 minutes prior to treatment with any IP) on Day 1 of Cycles 1, 2, 3, 4, and 7; and postdose (within 10 minutes after end of MEDI4736 infusion) on Day 1 of Cycles 1, 2, and 7

Outcome Measure Data

Analysis Population Description

The PK analysis set included all participants who received at least 1 dose of IP per protocol for whom any post-dose data were available and who did not violate or deviate from the protocol in ways that would significantly affect the PK analyses.

Arm/Group Title	Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
Measure Participants	20
Cycle 1 Day 1: Predose	10.60 (42.933)
Cycle 1 Day 1: Postdose	2236.29 (1678.496)
Cycle 2 Day 1: Predose	1829.36 (1473.533)
Cycle 2 Day 1: Postdose	24.40 (NA)
Cycle 3 Day 1: Predose	502.48 (601.914)
Cycle 4 Day 1: Predose	1345.00 (1068.666)
Cycle 7 Day 1: Predose	1200.00 (NA)
Cycle 7 Day 1: Postdose	7540.00 (NA)

Adverse Events

Time Frame	From initial IP administration (Day 1) until 90 days after the last dose of IP or initiation of the first subsequent anticancer therapy (whichever occurred first), approximately 30 months.
Adverse Event Reporting Description	The safety analysis set included all participants who received at least 1 dose of IP and for whom any post-dose data were available.
Arm/Group Title	Cohort 1 (MEDI4736 + Nab-paclitaxel + Gemcitabine)		Cohort 2 (MEDI4736 + AZD5069)
Arm/Group Description	Participants with metastatic PDAC who were treatment naive received MEDI4736 1.5 g IV infusion q4w. Participants also received nab-paclitaxel 125 mg/m^2 IV infusion followed by gemcitabine 1000 mg/m^2 IV infusion on Days 1, 8, and 15 of each 28-day cycle. Treatment continued until either confirmed PD unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.		Participants with metastatic PDAC with progression on the indicated types of chemotherapy received MEDI4736 1.5 g IV infusion q4w. Participants also received AZD5069 orally bid. The starting dose of 80 mg orally bid (with dose reductions to 40 mg or 20 mg for toxicity allowable). Treatment continued until either confirmed PD, unacceptable toxicity, withdrawal of consent, or another discontinuation criterion was met.
All Cause Mortality
	Cohort 1 (MEDI4736 + Nab-paclitaxel + Gemcitabine)		Cohort 2 (MEDI4736 + AZD5069)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		16/20 (80%)
Serious Adverse Events
	Cohort 1 (MEDI4736 + Nab-paclitaxel + Gemcitabine)		Cohort 2 (MEDI4736 + AZD5069)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)		16/20 (80%)
Blood and lymphatic system disorders
Febrile neutropenia	0/3 (0%)	0	1/20 (5%)	1
Gastrointestinal disorders
Constipation	1/3 (33.3%)	1	1/20 (5%)	1
Diarrhoea	0/3 (0%)	0	1/20 (5%)	1
Enterocolitis	0/3 (0%)	0	1/20 (5%)	1
Gastric haemorrhage	0/3 (0%)	0	1/20 (5%)	1
Nausea	0/3 (0%)	0	1/20 (5%)	1
Obstruction gastric	0/3 (0%)	0	1/20 (5%)	1
Upper gastrointestinal haemorrhage	0/3 (0%)	0	1/20 (5%)	3
Vomiting	0/3 (0%)	0	2/20 (10%)	2
General disorders
General physical health deterioration	0/3 (0%)	0	1/20 (5%)	1
Pyrexia	0/3 (0%)	0	1/20 (5%)	1
Hepatobiliary disorders
Cholangitis	0/3 (0%)	0	1/20 (5%)	1
Drug-induced liver injury	1/3 (33.3%)	1	0/20 (0%)	0
Hepatic failure	1/3 (33.3%)	1	0/20 (0%)	0
Hepatitis	0/3 (0%)	0	1/20 (5%)	1
Infections and infestations
Biliary sepsis	0/3 (0%)	0	1/20 (5%)	1
Lower respiratory tract infection	0/3 (0%)	0	1/20 (5%)	1
Neutropenic sepsis	0/3 (0%)	0	1/20 (5%)	1
Pneumonia	0/3 (0%)	0	1/20 (5%)	1
Streptococcal sepsis	0/3 (0%)	0	1/20 (5%)	1
Viral infection	0/3 (0%)	0	1/20 (5%)	1
Injury, poisoning and procedural complications
Infusion related reaction	0/3 (0%)	0	1/20 (5%)	1
Investigations
Neutrophil count decreased	0/3 (0%)	0	1/20 (5%)	3
Metabolism and nutrition disorders
Hypovolaemia	0/3 (0%)	0	1/20 (5%)	1
Musculoskeletal and connective tissue disorders
Pain in extremity	1/3 (33.3%)	1	0/20 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/3 (0%)	0	1/20 (5%)	1
Nervous system disorders
Ischaemic stroke	0/3 (0%)	0	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/3 (0%)	0	1/20 (5%)	1
Pleural effusion	0/3 (0%)	0	1/20 (5%)	1
Pneumonitis	1/3 (33.3%)	1	1/20 (5%)	1
Pulmonary embolism	0/3 (0%)	0	1/20 (5%)	1
Pulmonary oedema	0/3 (0%)	0	1/20 (5%)	1
Vascular disorders
Embolism	0/3 (0%)	0	1/20 (5%)	1
Other (Not Including Serious) Adverse Events
	Cohort 1 (MEDI4736 + Nab-paclitaxel + Gemcitabine)		Cohort 2 (MEDI4736 + AZD5069)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		20/20 (100%)
Blood and lymphatic system disorders
Anaemia	1/3 (33.3%)	1	1/20 (5%)	1
Leukopenia	1/3 (33.3%)	2	0/20 (0%)	0
Neutropenia	2/3 (66.7%)	6	2/20 (10%)	2
Cardiac disorders
Sinus tachycardia	0/3 (0%)	0	1/20 (5%)	1
Tachycardia	0/3 (0%)	0	1/20 (5%)	1
Ventricular extrasystoles	0/3 (0%)	0	1/20 (5%)	1
Endocrine disorders
Hypothyroidism	0/3 (0%)	0	1/20 (5%)	1
Eye disorders
Blindness unilateral	0/3 (0%)	0	1/20 (5%)	1
Gastrointestinal disorders
Abdominal distension	1/3 (33.3%)	1	2/20 (10%)	3
Abdominal pain	0/3 (0%)	0	6/20 (30%)	7
Abdominal pain upper	0/3 (0%)	0	3/20 (15%)	3
Aptyalism	0/3 (0%)	0	1/20 (5%)	1
Ascites	0/3 (0%)	0	1/20 (5%)	1
Colitis	1/3 (33.3%)	1	0/20 (0%)	0
Constipation	0/3 (0%)	0	4/20 (20%)	5
Diarrhoea	2/3 (66.7%)	2	4/20 (20%)	7
Dry mouth	0/3 (0%)	0	2/20 (10%)	2
Dyspepsia	0/3 (0%)	0	3/20 (15%)	3
Glossodynia	0/3 (0%)	0	1/20 (5%)	1
Melaena	0/3 (0%)	0	1/20 (5%)	1
Nausea	1/3 (33.3%)	1	8/20 (40%)	10
Parotid gland enlargement	0/3 (0%)	0	1/20 (5%)	1
Peptic ulcer	0/3 (0%)	0	1/20 (5%)	1
Rectal discharge	0/3 (0%)	0	1/20 (5%)	1
Steatorrhoea	0/3 (0%)	0	1/20 (5%)	1
Stomatitis	0/3 (0%)	0	5/20 (25%)	5
Tongue coated	0/3 (0%)	0	1/20 (5%)	1
Vomiting	1/3 (33.3%)	1	2/20 (10%)	10
General disorders
Administration site mass	0/3 (0%)	0	1/20 (5%)	1
Chills	1/3 (33.3%)	2	0/20 (0%)	0
Fatigue	2/3 (66.7%)	2	10/20 (50%)	11
Oedema peripheral	1/3 (33.3%)	1	2/20 (10%)	2
Pain	0/3 (0%)	0	1/20 (5%)	1
Peripheral swelling	0/3 (0%)	0	2/20 (10%)	2
Pyrexia	1/3 (33.3%)	1	1/20 (5%)	5
Hepatobiliary disorders
Hyperbilirubinaemia	0/3 (0%)	0	1/20 (5%)	1
Infections and infestations
Cellulitis	0/3 (0%)	0	1/20 (5%)	1
Escherichia urinary tract infection	0/3 (0%)	0	1/20 (5%)	1
Lower respiratory tract infection viral	0/3 (0%)	0	1/20 (5%)	1
Nasopharyngitis	0/3 (0%)	0	1/20 (5%)	1
Oral candidiasis	0/3 (0%)	0	5/20 (25%)	5
Pneumonia	0/3 (0%)	0	1/20 (5%)	1
Skin infection	0/3 (0%)	0	1/20 (5%)	1
Upper respiratory tract infection	0/3 (0%)	0	1/20 (5%)	1
Urinary tract infection	1/3 (33.3%)	1	0/20 (0%)	0
Injury, poisoning and procedural complications
Contusion	0/3 (0%)	0	2/20 (10%)	3
Fall	0/3 (0%)	0	3/20 (15%)	3
Skin wound	0/3 (0%)	0	1/20 (5%)	1
Soft tissue injury	0/3 (0%)	0	1/20 (5%)	1
Investigations
Blood alkaline phosphatase increased	0/3 (0%)	0	1/20 (5%)	3
Blood bicarbonate decreased	0/3 (0%)	0	1/20 (5%)	4
Blood creatinine increased	1/3 (33.3%)	1	0/20 (0%)	0
Blood glucose increased	0/3 (0%)	0	1/20 (5%)	1
Blood thyroid stimulating hormone increased	0/3 (0%)	0	1/20 (5%)	2
Body temperature increased	0/3 (0%)	0	1/20 (5%)	1
Citrobacter test positive	0/3 (0%)	0	1/20 (5%)	1
Electrocardiogram QT prolonged	0/3 (0%)	0	1/20 (5%)	2
Gamma-glutamyltransferase increased	0/3 (0%)	0	1/20 (5%)	3
Lymphocyte count decreased	0/3 (0%)	0	2/20 (10%)	3
Neutrophil count decreased	0/3 (0%)	0	1/20 (5%)	1
Prothrombin time prolonged	0/3 (0%)	0	1/20 (5%)	1
Weight decreased	0/3 (0%)	0	3/20 (15%)	4
Metabolism and nutrition disorders
Decreased appetite	1/3 (33.3%)	2	7/20 (35%)	8
Diabetes mellitus	1/3 (33.3%)	1	0/20 (0%)	0
Hypercalcaemia	0/3 (0%)	0	1/20 (5%)	1
Hyperglycaemia	0/3 (0%)	0	2/20 (10%)	2
Hypoalbuminaemia	0/3 (0%)	0	2/20 (10%)	5
Hypocalcaemia	1/3 (33.3%)	1	0/20 (0%)	0
Hypokalaemia	0/3 (0%)	0	1/20 (5%)	1
Hyponatraemia	1/3 (33.3%)	1	1/20 (5%)	2
Iron deficiency	0/3 (0%)	0	1/20 (5%)	1
Musculoskeletal and connective tissue disorders
Arthralgia	0/3 (0%)	0	1/20 (5%)	1
Back pain	0/3 (0%)	0	2/20 (10%)	2
Muscle spasms	1/3 (33.3%)	2	0/20 (0%)	0
Musculoskeletal chest pain	0/3 (0%)	0	1/20 (5%)	1
Musculoskeletal pain	0/3 (0%)	0	3/20 (15%)	3
Myalgia	1/3 (33.3%)	1	1/20 (5%)	1
Pain in extremity	0/3 (0%)	0	2/20 (10%)	2
Temporomandibular joint syndrome	0/3 (0%)	0	1/20 (5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	0/3 (0%)	0	2/20 (10%)	2
Tumour associated fever	0/3 (0%)	0	1/20 (5%)	1
Nervous system disorders
Disturbance in attention	0/3 (0%)	0	1/20 (5%)	1
Dizziness	0/3 (0%)	0	2/20 (10%)	2
Dysgeusia	0/3 (0%)	0	1/20 (5%)	1
Headache	1/3 (33.3%)	1	0/20 (0%)	0
Hypoaesthesia	0/3 (0%)	0	1/20 (5%)	1
Lethargy	0/3 (0%)	0	3/20 (15%)	3
Paraesthesia	0/3 (0%)	0	1/20 (5%)	1
Somnolence	0/3 (0%)	0	1/20 (5%)	1
Psychiatric disorders
Anxiety	0/3 (0%)	0	1/20 (5%)	1
Confusional state	0/3 (0%)	0	1/20 (5%)	1
Depressed mood	0/3 (0%)	0	2/20 (10%)	2
Depression	0/3 (0%)	0	2/20 (10%)	3
Insomnia	1/3 (33.3%)	1	0/20 (0%)	0
Renal and urinary disorders
Acute kidney injury	0/3 (0%)	0	1/20 (5%)	1
Haematuria	0/3 (0%)	0	1/20 (5%)	1
Pollakiuria	0/3 (0%)	0	1/20 (5%)	1
Polyuria	0/3 (0%)	0	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/3 (0%)	0	1/20 (5%)	1
Cough	0/3 (0%)	0	2/20 (10%)	3
Dysphonia	0/3 (0%)	0	1/20 (5%)	1
Dyspnoea	0/3 (0%)	0	2/20 (10%)	2
Oropharyngeal pain	0/3 (0%)	0	1/20 (5%)	1
Pulmonary embolism	0/3 (0%)	0	3/20 (15%)	3
Skin and subcutaneous tissue disorders
Alopecia	2/3 (66.7%)	2	1/20 (5%)	1
Night sweats	0/3 (0%)	0	2/20 (10%)	2
Pruritus	1/3 (33.3%)	1	0/20 (0%)	0
Rash	1/3 (33.3%)	1	1/20 (5%)	1
Rash maculo-papular	1/3 (33.3%)	1	0/20 (0%)	0
Skin mass	0/3 (0%)	0	1/20 (5%)	1
Vasculitic rash	0/3 (0%)	0	1/20 (5%)	2
Vascular disorders
Deep vein thrombosis	0/3 (0%)	0	1/20 (5%)	1
Vena cava thrombosis	0/3 (0%)	0	1/20 (5%)	1

Limitations/Caveats

Due to a programmatic decision, enrollment of additional participants to cohort 1 was not pursued. The study was terminated by sponsor.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.